Retinal neurodegeneration plays a significant role in the pathogenesis of diabetic retinopathy(DR),the leading cause of preventable blindness.In fact,the American Diabetes Association has defined DR as a highly specif...Retinal neurodegeneration plays a significant role in the pathogenesis of diabetic retinopathy(DR),the leading cause of preventable blindness.In fact,the American Diabetes Association has defined DR as a highly specific neurovascular complication(Solomon et al.,2017).Therefore,it is no longer acceptable to consider DR as merely a microvascular complication.In this regard,the term diabetic retinal disease(DRD)has been proposed as a broader term comprising microangiopathy and neurodegeneration.However,there are currently no treatments available that directly target the neurodegenerative changes of DR.This paper will give new insights into the translational research in this field with particular emphasis on glucagon-like peptide 1/dipeptidyl peptidase IV(GLP-1/DPP-IV)inhibitors.展开更多
Microtubules play a central role in cytoskeletal changes during neuronal development and maintenance.Microtubule dynamics is essential to polarity and shape transitions underlying neural cell division,differentiation,...Microtubules play a central role in cytoskeletal changes during neuronal development and maintenance.Microtubule dynamics is essential to polarity and shape transitions underlying neural cell division,differentiation,motility,and maturation.Kinesin superfamily protein 2A is a member of human kinesin 13 gene family of proteins that depolymerize and destabilize microtubules.In dividing cells,kinesin superfamily protein 2A is involved in mitotic progression,spindle assembly,and chromosome segregation.In postmitotic neurons,it is required for axon/dendrite specification and extension,neuronal migration,connectivity,and survival.Humans with kinesin superfamily protein 2A mutations suffer from a variety of malformations of cortical development,epilepsy,autism spectrum disorder,and neurodegeneration.In this review,we discuss how kinesin superfamily protein 2A regulates neuronal development and function,and how its deregulation causes neurodevelopmental and neurological disorders.展开更多
Neuroinflammation and neurodegeneration are key processes that mediate the development and progression of neurological diseases.However,the mechanisms modulating these processes in different diseases remain incomplete...Neuroinflammation and neurodegeneration are key processes that mediate the development and progression of neurological diseases.However,the mechanisms modulating these processes in different diseases remain incompletely understood.Advances in single cell based multi-omic analyses have helped to identify distinct molecular signatures such as Lgals3 that is associated with neuroinflammation and neurodegeneration in the central nervous system(CNS).Lgals3 encodes galectin-3(Gal3),aβ-galactoside and glycan binding glycoprotein that is frequently upregulated by reactive microglia/macrophages in the CNS during various neurological diseases.While Gal3 has previously been associated with non-CNS inflammatory and fibrotic diseases,recent studies highlight Gal3 as a prominent regulator of inflammation and neuroaxonal damage in the CNS during diseases such as multiple sclerosis,Alzheimer’s disease,and Parkinson’s disease.In this review,we summarize the pleiotropic functions of Gal3 and discuss evidence that demonstrates its detrimental role in neuroinflammation and neurodegeneration during different neurological diseases.We also consider the challenges of translating preclinical observations into targeting Gal3 in the human CNS.展开更多
Trimethyltin chloride(TMT)is a potent neurotoxin to cause neurodegeneration,especially in hippocampus.This study aimed to identify dietary components that can effectively attenuate TMT-induced neurodegeneration in hum...Trimethyltin chloride(TMT)is a potent neurotoxin to cause neurodegeneration,especially in hippocampus.This study aimed to identify dietary components that can effectively attenuate TMT-induced neurodegeneration in humans.The predominant anthocyanin in human diets,cyanidin-3-O-glucoside(C3G,5 or 50 mg/kg),was given to mice for 16 days,and TMT(2.7 mg/kg)was injected intraperitoneally once on the eighth day.C3G(50 mg/kg)significantly alleviated TMT-induced seizures and subsequent cognitive impairment by ameliorating hippocampal neurodegeneration and synaptic dysfunction.Furthermore,C3G treatment restored glutamate homeostasis in brain and reversed glutamine synthetase(GS)inhibition in reactive astrogliosis and neuroinflammation,which are critical for C3G's neuroprotective effects.Notably,C3G decreased the lipopolysaccharide,tumor necrosis factor-α,interleukin-6,and interleukin-1βlevels in the mice,which potentially by modulating the relative abundance of Atopobiaceae and Lachnospiraceae in the gut.C3G may be a promising and practical dietary component for reducing TMT-induced neurodegeneration.展开更多
Mitochondria are cytoplasmic organelles referred to as the powerhouse of the cell because they are primarily involved in oxidative phosphorylation and energy production.They are particularly abundant in tissues with h...Mitochondria are cytoplasmic organelles referred to as the powerhouse of the cell because they are primarily involved in oxidative phosphorylation and energy production.They are particularly abundant in tissues with high energy demands,including muscle,liver,and brain,and mitochondrial dysfunction,oxidative mitochondrial DNA(mtDNA)damage,and impaired mitochondrial dynamics have often been associated with neurodegeneration.展开更多
Lipid peroxidation and iron accumulation are closely associated with neurodegenerative diseases,such as Alzheimer’s,Parkinson’s,and Huntington’s diseases,or neurodegeneration with brain iron accumulation disorders....Lipid peroxidation and iron accumulation are closely associated with neurodegenerative diseases,such as Alzheimer’s,Parkinson’s,and Huntington’s diseases,or neurodegeneration with brain iron accumulation disorders.Mitochondrial dysfunction,lipofuscin accumulation,autophagy disruption,and ferroptosis have been implicated as the critical pathomechanisms of lipid peroxidation and iron accumulation in these disorders.Currently,the connection between lipid peroxidation and iron accumulation and the initial cause or consequence in neurodegeneration processes is unclear.In this review,we have compiled the known mechanisms by which lipid peroxidation triggers iron accumulation and lipofuscin formation,and the effect of iron overload on lipid peroxidation and cellular function.The vicious cycle established between both pathological alterations may lead to the development of neurodegeneration.Therefore,the investigation of these mechanisms is essential for exploring therapeutic strategies to restrict neurodegeneration.In addition,we discuss the interplay between lipid peroxidation and iron accumulation in neurodegeneration,particularly in PLA2G6-associated neurodegeneration,a rare neurodegenerative disease with autosomal recessive inheritance,which belongs to the group of neurodegeneration with brain iron accumulation disorders.展开更多
In recent years, multiple disciplines have focused on mitochondrial biology and contributed to understanding its relevance towards adult-onset neurodegenerative disorders. These are complex dynamic organelles that hav...In recent years, multiple disciplines have focused on mitochondrial biology and contributed to understanding its relevance towards adult-onset neurodegenerative disorders. These are complex dynamic organelles that have a variety of functions in ensuring cellular health and homeostasis. The plethora of mitochondrial functionalities confers them an intrinsic susceptibility to internal and external stressors(such as mutation accumulation or environmental toxins), particularly so in long-lived postmitotic cells such as neurons. Thus, it is reasonable to postulate an involvement of mitochondria in aging-associated neurological disorders, notably neurodegenerative pathologies including Alzheimer’s disease and Parkinson’s disease. On the other hand, biological effects resulting from neurodegeneration can in turn affect mitochondrial health and function, promoting a feedback loop further contributing to the progression of neuronal dysfunction and cellular death. This review examines state-of-the-art knowledge, focus on current research exploring mitochondrial health as a contributing factor to neuroregeneration, and the development of therapeutic approaches aimed at restoring mitochondrial homeostasis in a pathological setting.展开更多
Neurodegenerative diseases are caused by the progressive loss of specific neurons.The exact mechanisms of action of these diseases are unknown,and many studies have focused on pathways related to abnormal accumulation...Neurodegenerative diseases are caused by the progressive loss of specific neurons.The exact mechanisms of action of these diseases are unknown,and many studies have focused on pathways related to abnormal accumulation and processing of proteins,mitochondrial dysfunction,and oxidative stress leading to apoptotic death.However,a growing body of evidence indicates that aberrant cell cycle re-entry plays a major role in the pathogenesis of neurodegeneration.The activation of the cell cycle in mature neurons could be promoted by several signaling mechanisms,including c-Jun N-terminal kinases,p38 mitogen-activated protein kinases,and mitogen-activated protein kinase/extracellular signal-regulated kinase cascades;post-translational modifications such as Tau-phosphorylation;and DNA damage response.In all these events,implicated Cdk5,a proline-directed serine/threonine protein kinase,seems to be responsible for several cellular processes in neurons including axon growth,neurotransmission,synaptic plasticity,neuronal migration,and maintenance of neuronal survival.However,under pathological conditions,Cdk5 dysregulation may lead to cell cycle re-entry in post-mitotic neurons.Thus,Cdk5 hyperactivation,by its physiologic activator p25,hyper-phosphorylates downstream substrates related to neurodegenerative diseases.This review summarizes factors such as oxidative stress,DNA damage response,signaling pathway disturbance,and Ubiquitin proteasome malfunction contributing to cell cycle re-entry in post-mitotic neurons.It also describes how all these factors are linked to a greater or lesser extent with Cdk5.Thus,it offers a global vision of the function of cell cycle-related proteins in mature neurons with a focus on Cdk5 and how this protein contributes to the development of Alzheimer’s disease,Parkinson’s disease,amyotrophic lateral sclerosis,and Huntington’s disease by cell cycle activation.展开更多
In light of the rising evidence of the association between viral and bacterial infections and neurodegeneration,we aimed at revisiting the infectious hypothesis of Alzheimer’s disease and analyzing the possible impli...In light of the rising evidence of the association between viral and bacterial infections and neurodegeneration,we aimed at revisiting the infectious hypothesis of Alzheimer’s disease and analyzing the possible implications of COVID-19 neurological sequelae in long-term neurodegeneration.We wondered how SARS-CoV-2 could be related to the amyloid-βcascade and how it could lead to the pathological hallmarks of the disease.We also predict a paradigm change in clinical medicine,which now has a great opportunity to conduct prospective surveillance of cognitive sequelae and progression to dementia in people who suffered severe infections together with other risk factors for Alzheimer’s disease.展开更多
Developmental motifs in neurodegeneration:Neurodegeneration,the prominent feature of neurodegenerative disease,is characterized by the progressive and selective loss of neuronal function.As some of the pathologies cau...Developmental motifs in neurodegeneration:Neurodegeneration,the prominent feature of neurodegenerative disease,is characterized by the progressive and selective loss of neuronal function.As some of the pathologies caused by neurodegeneration may be irreversible,early intervention will be required for the treatments that aim to slow or halt the manifestation of these diseases.Traditionally,neurodegeneration evokes the idea of a progressive decline of brain function.展开更多
AIM:To evaluate the effects of metabolic syndrome(Met S)on retinal neurodegeneration by optical coherence tomography(OCT).METHODS:Patients diagnosed as Met S were compared with the age and sex-matched healthy control ...AIM:To evaluate the effects of metabolic syndrome(Met S)on retinal neurodegeneration by optical coherence tomography(OCT).METHODS:Patients diagnosed as Met S were compared with the age and sex-matched healthy control group(CG).Waist circumference measurements,fasting serological biochemical tests,and systemic blood pressures of all participants were evaluated.The Met S group was divided into 3 subgroups according to the number of Met S components:hypertension,diabetes mellitus,dyslipidemia(low-,high-density lipoprotein,hypertriglyceridemia),and visceral obesity findings;3-component Met S3,4-component Met S4,and all-component Met S5.All patients underwent complete eye examination and spectral OCT retinal imaging.RESULTS:Totally 58 eyes of 58 patients were included in the Met S group and 63 eyes of 63 age and sex-matched healthy subjects were included in CG.Met S group was composed of 22 subjects in Met S3,21 subjects in Met S4,and 15 subjects in the Met S5 subgroup.Mean foveal thickness(Met S,218.7±23.1μm vs CG,228.8±21.9μm,P=0.015),mean inferior(Met S,283.4±17.0μm vs CG,288.7±38.4μm,P=0.002),superior(Met S,287.0±18.5μm vs CG 297.3±17.1μm,P=0.001),nasal(Met S 287.3±16.7μm vs CG 297.9±13.9μm,P=0.000)and temporal(274.5±17.6μm vs CG 285.6±13.6μm,P=0.000)thickness in the 3 mm Early Treatment of Diabetic Retinopathy Study(ETDRS)circle was significantly lower in the Met S group.There was no statistically significant difference in the mean inferior,superior,nasal,and temporal thickness of 6 mm ETDRS circle,total macular volume,peripapillary and macular retinal nerve fiber layer,macular ganglion cell layer with inner plexiform layer,and ganglion cell complex.No statistically significant difference was found in these values between the Met S3,Met S4,and the Met S5 groups.CONCLUSION:A significant reduction in central macular region thickness in Met S is detected and macular thickness is more susceptible to Met S induced neurodegeneration than peripapillary retinal nerve fiber layer.展开更多
Diabetic retinopathy(DR) has been classically considered to be a microcirculatory disease of the retina caused by the deleterious metabolic effects of hyperglycemia per se and the metabolic pathways triggered by hyper...Diabetic retinopathy(DR) has been classically considered to be a microcirculatory disease of the retina caused by the deleterious metabolic effects of hyperglycemia per se and the metabolic pathways triggered by hyperglycemia.However,retinal neurodegeneration is already present before any microcirculatory abnormalities can be detected in ophthalmoscopic examination.In other words,retinal neurodegeneration is an early event in the pathogenesis of DR which predates and participates in the microcirculatory abnormalities that occur in DR.Therefore,the study of the mechanisms that lead to neurodegeneration will be essential to identify new therapeutic targets in the early stages of DR.Elevated levels of glutamate and the overexpression of the renin-angiotensin-system play an essential role in the neurodegenerative process that occurs in diabetic retina.Among neuroprotective factors,pigment epithelial derived factor,somatostatin and erythropoietin seem to be the most relevant and these will be considered in this review.Nevertheless,it should be noted that the balance between neurotoxic and neuroprotective factors rather than levels of neurotoxic factors alone will determine the presence or absence of retinal neurodegeneration in the diabetic eye.New strategies,based on either the delivery of neuroprotective agents or the blockade of neurotoxic factors,are currently being tested in experimental models and in clinical pilot studies.Whether these novel therapies will eventually supplement or prevent the need for laser photocoagulation or vitrectomy awaits the results of additional clinical research.展开更多
All retinoids, which can be natural and synthetic, are chemically related to vitamin A. Both natural and synthetic retinoids use specific nuclear receptors such as retinoic acid receptors and retinoid X receptors to a...All retinoids, which can be natural and synthetic, are chemically related to vitamin A. Both natural and synthetic retinoids use specific nuclear receptors such as retinoic acid receptors and retinoid X receptors to activate specific signaling pathways in the cells. Retinoic acid signaling is extremely important in the central nervous system. Impairment of retinoic acid signaling pathways causes severe pathological processes in the central nervous system, especially in the adult brain. Retinoids have major roles in neural patterning, differentiation, axon outgrowth in normal development, and function of the brain. Impaired retinoic acid signaling results in neuroinflammation, oxidative stress, mitochondrial malfunction, and neurodegeneration leading to progressive Alzheimer’s disease, which is pathologically characterized by extra-neuronal accumulation of amyloid plaques(aggregated amyloid-beta) and intra-neurofibrillary tangles(hyperphosphorylated tau protein) in the temporal lobe of the brain. Alzheimer’s disease is the most common cause of dementia and loss of memory in old adults. Inactive cholinergic neurotransmission is responsible for cognitive deficits in Alzheimer’s disease patients. Deficiency or deprivation of retinoic acid in mice is associated with loss of spatial learning and memory. Retinoids inhibit expression of chemokines and neuroinflammatory cytokines in microglia and astrocytes, which are activated in Alzheimer’s disease. Stimulation of retinoic acid receptors and retinoid X receptors slows down accumulation of amyloids, reduces neurodegeneration, and thereby prevents pathogenesis of Alzheimer’s disease in mice. In this review, we described chemistry and biochemistry of some natural and synthetic retinoids and potentials of retinoids for prevention of neuroinflammation and neurodegeneration in Alzheimer’s disease.展开更多
Diabetes is a lifelong disease characterized by glucose metabolic imbalance,in which low insulin levels or impaired insulin signaling lead to hyperglycemic state.Within 20 years of diabetes progression,95%of patients ...Diabetes is a lifelong disease characterized by glucose metabolic imbalance,in which low insulin levels or impaired insulin signaling lead to hyperglycemic state.Within 20 years of diabetes progression,95%of patients will have diabetic retinopathy,the leading cause of visual defects in working-age people worldwide.Although diabetes is considered a microvascular disease,recent studies have shown that neurodegeneration precedes vascular changes within the diabetic visual system,albeit its mechanisms are still under investigation.Neuroinflammation and oxidative stress are intrinsically related phenomena,since macrophage/microglia and astrocytes are the main sources of reactive oxygen species during central nervous system chronic degenerative diseases,and both pathological processes are increased in the visual system during diabetes.The present review will focus on recent findings of the contribution of oxidative stress derived from neuroinflammation in the early neurodegenerative aspects of the diabetic visual system and their relationship with galectin-3.展开更多
Cardiovascular disease, nervous system disorders, and cancer in association with other diseases such as diabetes mellitus result in greater than sixty percent of the global annual deaths. These noncommunicable disease...Cardiovascular disease, nervous system disorders, and cancer in association with other diseases such as diabetes mellitus result in greater than sixty percent of the global annual deaths. These noncommunicable diseases also affect at least one-third of the population in low and middle-income countries and lead to hypertension, elevated cholesterol, malignancy, and neurodegenerative disorders such as Alzheimer's disease and stroke. With the climbing lifespan of the world's population, increased prevalence of these disorders is expected requiring the development of new therapeutic strategies against these disabling disease entities. Targeting stem cellproliferation for cardiac disease, vascular disorders, cancer, and neurodegenerative disorders is receiving great enthusiasm, especially those that focus upon SIRT1, a mammalian homologue of the yeast silent information regulator-2. Modulation of the cellular activity of SIRT1 can involve oversight by nicotinamide/nicotinic acid mononucleotide adenylyltransferase, mammalian forkhead transcription factors, mechanistic of rapamycin pathways, and cysteine-rich protein 61, connective tissue growth factor, and nephroblastoma over-expressed gene family members that can impact cytoprotective outcomes. Ultimately, the ability of SIRT1 to control the programmed cell death pathways of apoptosis and autophagy can determine not only cardiac, vascular, and neuronal stem cell development and longevity, but also the onset of tumorigenesis and the resistance against chemotherapy. SIRT1 therefore has a critical role and holds exciting prospects for new therapeutic strategies that can offer reparative processes for cardiac, vascular, and nervous system degenerative disorders as well as targeted control of aberrant cell growth during cancer.展开更多
Artemisinin,also called qinghaosu,is originally derived from the sweet wormwood plant(Artemisia annua),which is used in traditional Chinese medicine.Artemisinin and its derivatives(artemisinins)have been widely used f...Artemisinin,also called qinghaosu,is originally derived from the sweet wormwood plant(Artemisia annua),which is used in traditional Chinese medicine.Artemisinin and its derivatives(artemisinins)have been widely used for many years as anti-malarial agents,with few adverse side effects.Interestingly,evidence has recently shown that artemisinins might have a therapeutic value for several other diseases beyond malaria,including cancers,inflammatory diseases,and autoimmune disorders.Neurodegeneration is a challenging age-associated neurological disorder characterized by deterioration of neuronal structures as well as functions,whereas neuroinflammation has been considered to be an underlying factor in the development of various neurodegenerative disorders,including Alzheimer’s disease.Recently discovered properties of artemisinins suggested that they might be used to treat neurodegenerative disorders by decreasing oxidation,inflammation,and amyloid beta protein(Aβ).In this review,we will introduce artemisinins and highlight the possible mechanisms of their neuroprotective activities,suggesting that artemisinins might have therapeutic potential in neurodegenerative disorders.展开更多
Neuroinflammation and neurodegeneration are key components in the establishment and progression of neurodegenerative diseases including Alzheimer's Disease(AD). Over the past decade increasing evidence is emerging...Neuroinflammation and neurodegeneration are key components in the establishment and progression of neurodegenerative diseases including Alzheimer's Disease(AD). Over the past decade increasing evidence is emerging for the use of components of the canonical autophagy machinery in pathways that are characterized by LC3 lipidation yet are distinct from traditional macro-autophagy. One such pathway that utilizes components of the autophagy machinery to target LC3 to endosomes, a process termed LC3-associated endocytosis(LANDO), has recently been identified and regulates neuroinflammation. Abrogation of LANDO in microglia cells results in a propensity for elevated neuroinflammatory cytokine production. Using the well-established 5 xFAD model of AD to interrogate neuroinflammatory regulation, impairment of LANDO through deletion of a key upstream regulator Rubicon or other downstream autophagy components, exacerbated disease onset and severity, while deletion of microglial autophagy alone had no measurable effect. Mice presented with robust deposition of the neurotoxic AD protein β-amyloid(Aβ), microglial activation and inflammatory cytokine production, tau phosphorylation, and aggressive neurodegeneration culminating in severe memory impairment. LANDO-deficiency impaired recycling of receptors that recognize Aβ, including TLR4 and TREM2. LANDO-deficiency alone through deletion of the WD-domain of the autophagy protein ATG16 L, revealed a role for LANDO in the spontaneous establishment of age-associated AD. LANDO-deficient mice aged to 2 years presented with advanced ADlike disease and pathology correlative to that observed in human AD patients. Together, these studies illustrate an important role for microglial LANDO in regulating CNS immune activation and protection against neurodegeneration. New evidence is emerging that demonstrates a putative linkage between pathways such as LANDO and cell death regulation via apoptosis and possibly necroptosis. Herein, we provide a review of the use of the autophagy machinery in non-canonical mechanisms that alter immune regulation and could have significant impact in furthering our understanding of not only CNS diseases like AD, but likely beyond.展开更多
●AIM:To observe the effect of inhibiting long non-coding RNA(lncRNA)metastasis-associated lung adenocarcinoma transcript 1(MALAT1)on diabetic neurodegeneration.●METHODS:Thirty-six 8-week-old C57 BL/6 mice were rando...●AIM:To observe the effect of inhibiting long non-coding RNA(lncRNA)metastasis-associated lung adenocarcinoma transcript 1(MALAT1)on diabetic neurodegeneration.●METHODS:Thirty-six 8-week-old C57 BL/6 mice were randomly divided into normal control,diabetic control,diabetic scrambled small interfering RNAs(siRNAs)and diabetic MALAT1-siRNA groups.After diabetic induction with streptozocin intraperitoneally-injection,the diabetic M A L AT 1-s i R N A g ro u p w a s i n t r av i t r e a l l y i n j e c te d with 1μL 20μmol/L MALAT1 siRNA,and the diabetic scrambled siRNA group was injected with the same amount of scrambled siRNA.Electroretinography was performed to examine photoreceptor functions 16 wk after diabetes induction.MALAT1 expression was detected via real time polymerase chain reaction.Cone morphological changes were examined using immunofluorescence.Rod morphological changes were examined by determining outer nuclear layer(ONL)thickness.●RESULTS:The upregulation of retinal MALAT1 expression was detected in the diabetic control mice,while MALAT1 expression in the diabetic MALAT1-siRNA mice was decreased by 91.48%compared to diabetic control mice.The diabetic MALAT1-siRNA and diabetic control mice showed lower a-wave and b-wave amplitudes than did the normal control mice in scotopic and photopic electroretinogram,while the diabetic MALAT1-siRNA mice showed higher amplitudes than diabetic control mice.Morphological examination revealed that ONL thickness in the diabetic MALAT1-siRNA and diabetic control mice was lower than normal control mice.However,ONL thickness was greater in the diabetic MALAT1-siRNA mice than diabetic control mice.Moreover,the diabetic control mice performed a sparser cone cell arrangement and shorter outer segment morphology than diabetic MALAT1-siRNA mice.●CONCLUSION:Inhibiting retinal MALAT1 results in mitigative effects on the retinal photoreceptors,thus alleviating diabetic neurodegeneration.展开更多
Cellular homeostasis requires a tightly controlled balance between protein synthesis, folding and degradation. Especially long-lived, post-mitotic cells such as neurons depend on an efficient proteostasis system to ma...Cellular homeostasis requires a tightly controlled balance between protein synthesis, folding and degradation. Especially long-lived, post-mitotic cells such as neurons depend on an efficient proteostasis system to maintain cellular health over decades. Thus, a functional decline of processes contributing to protein degradation such as autophagy and general lysosomal proteolytic capacity is connected to several age-associated neurodegenerative disorders, including Parkinson's, Alzheimer's and Huntington's diseases. These so called proteinopathies are characterized by the accumulation and misfolding of distinct proteins, subsequently driving cellular demise. We recently linked efficient lysosomal protein breakdown via the protease cathepsin D to the Ca^(2+)/calmodulin-dependent phosphatase calcineurin. In a yeast model for Parkinson's disease, functional calcineurin was required for proper trafficking of cathepsin D to the lysosome and for recycling of its endosomal sorting receptor to allow further rounds of shuttling. Here, we discuss these findings in relation to present knowledge about the involvement of cathepsin D in proteinopathies in general and a possible connection between this protease, calcineurin signalling and endosomal sorting in particular. As dysregulation of Ca^(2+) homeostasis as well as lysosomal impairment is connected to a plethora of neurodegenerative disorders, this novel interplay might very well impact pathologies beyond Parkinson's disease.展开更多
Multiple sclerosis is an autoimmune disease in which the immune system attacks the myelin sheath in the central nervous system.It is characterized by blood-brain barrier dysfunction throughout the course of multiple s...Multiple sclerosis is an autoimmune disease in which the immune system attacks the myelin sheath in the central nervous system.It is characterized by blood-brain barrier dysfunction throughout the course of multiple sclerosis, followed by the entry of immune cells and activation of local microglia and astrocytes.Glial cells(microglia, astrocytes, and oligodendrocyte lineage cells) are known as the important mediators of neuroinflammation, all of which play major roles in the pathogenesis of multiple sclerosis.Network communications between glial cells affect the activities of oligodendrocyte lineage cells and influence the demyelination-remyelination process.A finely balanced glial response may create a favorable lesion environment for efficient remyelination and neuroregeneration.This review focuses on glial response and neurodegeneration based on the findings from multiple sclerosis and major rodent demyelination models.In particular, glial interaction and molecular crosstalk are discussed to provide insights into the potential cell-and molecule-specific therapeutic targets to improve remyelination and neuroregeneration.展开更多
基金funded by grants from the Instituto de Salud CarlosⅢ(DTS18/0163 and ICI20/00129)co-funded by European Union。
文摘Retinal neurodegeneration plays a significant role in the pathogenesis of diabetic retinopathy(DR),the leading cause of preventable blindness.In fact,the American Diabetes Association has defined DR as a highly specific neurovascular complication(Solomon et al.,2017).Therefore,it is no longer acceptable to consider DR as merely a microvascular complication.In this regard,the term diabetic retinal disease(DRD)has been proposed as a broader term comprising microangiopathy and neurodegeneration.However,there are currently no treatments available that directly target the neurodegenerative changes of DR.This paper will give new insights into the translational research in this field with particular emphasis on glucagon-like peptide 1/dipeptidyl peptidase IV(GLP-1/DPP-IV)inhibitors.
基金Fund for Scientific Research(FNRS)PDR T0236.20FNRS-Exellence of Science 30913351FNRS CDR J.0175.23(to FT)。
文摘Microtubules play a central role in cytoskeletal changes during neuronal development and maintenance.Microtubule dynamics is essential to polarity and shape transitions underlying neural cell division,differentiation,motility,and maturation.Kinesin superfamily protein 2A is a member of human kinesin 13 gene family of proteins that depolymerize and destabilize microtubules.In dividing cells,kinesin superfamily protein 2A is involved in mitotic progression,spindle assembly,and chromosome segregation.In postmitotic neurons,it is required for axon/dendrite specification and extension,neuronal migration,connectivity,and survival.Humans with kinesin superfamily protein 2A mutations suffer from a variety of malformations of cortical development,epilepsy,autism spectrum disorder,and neurodegeneration.In this review,we discuss how kinesin superfamily protein 2A regulates neuronal development and function,and how its deregulation causes neurodevelopmental and neurological disorders.
文摘Neuroinflammation and neurodegeneration are key processes that mediate the development and progression of neurological diseases.However,the mechanisms modulating these processes in different diseases remain incompletely understood.Advances in single cell based multi-omic analyses have helped to identify distinct molecular signatures such as Lgals3 that is associated with neuroinflammation and neurodegeneration in the central nervous system(CNS).Lgals3 encodes galectin-3(Gal3),aβ-galactoside and glycan binding glycoprotein that is frequently upregulated by reactive microglia/macrophages in the CNS during various neurological diseases.While Gal3 has previously been associated with non-CNS inflammatory and fibrotic diseases,recent studies highlight Gal3 as a prominent regulator of inflammation and neuroaxonal damage in the CNS during diseases such as multiple sclerosis,Alzheimer’s disease,and Parkinson’s disease.In this review,we summarize the pleiotropic functions of Gal3 and discuss evidence that demonstrates its detrimental role in neuroinflammation and neurodegeneration during different neurological diseases.We also consider the challenges of translating preclinical observations into targeting Gal3 in the human CNS.
基金supported by the National Natural Science Foundation of China(81903275)the fund of Cultivation Project of Double First-Class Disciplines of Food Science and Engineering,Beijing Technology&Business University(BTBUYXTD202203)。
文摘Trimethyltin chloride(TMT)is a potent neurotoxin to cause neurodegeneration,especially in hippocampus.This study aimed to identify dietary components that can effectively attenuate TMT-induced neurodegeneration in humans.The predominant anthocyanin in human diets,cyanidin-3-O-glucoside(C3G,5 or 50 mg/kg),was given to mice for 16 days,and TMT(2.7 mg/kg)was injected intraperitoneally once on the eighth day.C3G(50 mg/kg)significantly alleviated TMT-induced seizures and subsequent cognitive impairment by ameliorating hippocampal neurodegeneration and synaptic dysfunction.Furthermore,C3G treatment restored glutamate homeostasis in brain and reversed glutamine synthetase(GS)inhibition in reactive astrogliosis and neuroinflammation,which are critical for C3G's neuroprotective effects.Notably,C3G decreased the lipopolysaccharide,tumor necrosis factor-α,interleukin-6,and interleukin-1βlevels in the mice,which potentially by modulating the relative abundance of Atopobiaceae and Lachnospiraceae in the gut.C3G may be a promising and practical dietary component for reducing TMT-induced neurodegeneration.
文摘Mitochondria are cytoplasmic organelles referred to as the powerhouse of the cell because they are primarily involved in oxidative phosphorylation and energy production.They are particularly abundant in tissues with high energy demands,including muscle,liver,and brain,and mitochondrial dysfunction,oxidative mitochondrial DNA(mtDNA)damage,and impaired mitochondrial dynamics have often been associated with neurodegeneration.
基金supported by FIS PI16/00786(2016)and FIS PI19/00377(2019)grantsthe Ministerio de Sanidad,Spain and the Fondo Europeo de Desarrollo Regional(FEDER Unión Europea)Spanish Ministry of Education,Culture and Sport.This activity has been co-financed by the European Regional Development Fund(ERDF)and by the Regional Ministry of Economic Transformation,Industry,Knowledge and Universities of the Junta de Andalucía,within the framework of the ERDF Andalusia operational program 2014-2020 Thematic objective“01-Reinforcement of research,technological development and innovation”through the reference research project CTS-5725 and PY18-850(to JASA).
文摘Lipid peroxidation and iron accumulation are closely associated with neurodegenerative diseases,such as Alzheimer’s,Parkinson’s,and Huntington’s diseases,or neurodegeneration with brain iron accumulation disorders.Mitochondrial dysfunction,lipofuscin accumulation,autophagy disruption,and ferroptosis have been implicated as the critical pathomechanisms of lipid peroxidation and iron accumulation in these disorders.Currently,the connection between lipid peroxidation and iron accumulation and the initial cause or consequence in neurodegeneration processes is unclear.In this review,we have compiled the known mechanisms by which lipid peroxidation triggers iron accumulation and lipofuscin formation,and the effect of iron overload on lipid peroxidation and cellular function.The vicious cycle established between both pathological alterations may lead to the development of neurodegeneration.Therefore,the investigation of these mechanisms is essential for exploring therapeutic strategies to restrict neurodegeneration.In addition,we discuss the interplay between lipid peroxidation and iron accumulation in neurodegeneration,particularly in PLA2G6-associated neurodegeneration,a rare neurodegenerative disease with autosomal recessive inheritance,which belongs to the group of neurodegeneration with brain iron accumulation disorders.
基金supported by a grant from the Fundacao para a Ciencia e Tecnologia of the Ministerio da Educacao e Ciencia (2020.02006.CEECIND)iBiMED,University of Aveiro and the Fundacao para a Ciência e Tecnologia of the Ministerio da Educacao e Ciencia (to DT)。
文摘In recent years, multiple disciplines have focused on mitochondrial biology and contributed to understanding its relevance towards adult-onset neurodegenerative disorders. These are complex dynamic organelles that have a variety of functions in ensuring cellular health and homeostasis. The plethora of mitochondrial functionalities confers them an intrinsic susceptibility to internal and external stressors(such as mutation accumulation or environmental toxins), particularly so in long-lived postmitotic cells such as neurons. Thus, it is reasonable to postulate an involvement of mitochondria in aging-associated neurological disorders, notably neurodegenerative pathologies including Alzheimer’s disease and Parkinson’s disease. On the other hand, biological effects resulting from neurodegeneration can in turn affect mitochondrial health and function, promoting a feedback loop further contributing to the progression of neuronal dysfunction and cellular death. This review examines state-of-the-art knowledge, focus on current research exploring mitochondrial health as a contributing factor to neuroregeneration, and the development of therapeutic approaches aimed at restoring mitochondrial homeostasis in a pathological setting.
基金supported by the Spanish Ministry of Industry and Competitiveness[Grant BFU2016-80006-P]The Andalusian Regional Government[Group BIO-216]the FEDER-Andalusian programme 2014-2020[1262530-R].
文摘Neurodegenerative diseases are caused by the progressive loss of specific neurons.The exact mechanisms of action of these diseases are unknown,and many studies have focused on pathways related to abnormal accumulation and processing of proteins,mitochondrial dysfunction,and oxidative stress leading to apoptotic death.However,a growing body of evidence indicates that aberrant cell cycle re-entry plays a major role in the pathogenesis of neurodegeneration.The activation of the cell cycle in mature neurons could be promoted by several signaling mechanisms,including c-Jun N-terminal kinases,p38 mitogen-activated protein kinases,and mitogen-activated protein kinase/extracellular signal-regulated kinase cascades;post-translational modifications such as Tau-phosphorylation;and DNA damage response.In all these events,implicated Cdk5,a proline-directed serine/threonine protein kinase,seems to be responsible for several cellular processes in neurons including axon growth,neurotransmission,synaptic plasticity,neuronal migration,and maintenance of neuronal survival.However,under pathological conditions,Cdk5 dysregulation may lead to cell cycle re-entry in post-mitotic neurons.Thus,Cdk5 hyperactivation,by its physiologic activator p25,hyper-phosphorylates downstream substrates related to neurodegenerative diseases.This review summarizes factors such as oxidative stress,DNA damage response,signaling pathway disturbance,and Ubiquitin proteasome malfunction contributing to cell cycle re-entry in post-mitotic neurons.It also describes how all these factors are linked to a greater or lesser extent with Cdk5.Thus,it offers a global vision of the function of cell cycle-related proteins in mature neurons with a focus on Cdk5 and how this protein contributes to the development of Alzheimer’s disease,Parkinson’s disease,amyotrophic lateral sclerosis,and Huntington’s disease by cell cycle activation.
基金supported by grants to DD from Agencia Nacional de Promoción de la Investigación,el desarrollo tecnológico y la innovación(ANPCyT,PICT N°03893).
文摘In light of the rising evidence of the association between viral and bacterial infections and neurodegeneration,we aimed at revisiting the infectious hypothesis of Alzheimer’s disease and analyzing the possible implications of COVID-19 neurological sequelae in long-term neurodegeneration.We wondered how SARS-CoV-2 could be related to the amyloid-βcascade and how it could lead to the pathological hallmarks of the disease.We also predict a paradigm change in clinical medicine,which now has a great opportunity to conduct prospective surveillance of cognitive sequelae and progression to dementia in people who suffered severe infections together with other risk factors for Alzheimer’s disease.
文摘Developmental motifs in neurodegeneration:Neurodegeneration,the prominent feature of neurodegenerative disease,is characterized by the progressive and selective loss of neuronal function.As some of the pathologies caused by neurodegeneration may be irreversible,early intervention will be required for the treatments that aim to slow or halt the manifestation of these diseases.Traditionally,neurodegeneration evokes the idea of a progressive decline of brain function.
文摘AIM:To evaluate the effects of metabolic syndrome(Met S)on retinal neurodegeneration by optical coherence tomography(OCT).METHODS:Patients diagnosed as Met S were compared with the age and sex-matched healthy control group(CG).Waist circumference measurements,fasting serological biochemical tests,and systemic blood pressures of all participants were evaluated.The Met S group was divided into 3 subgroups according to the number of Met S components:hypertension,diabetes mellitus,dyslipidemia(low-,high-density lipoprotein,hypertriglyceridemia),and visceral obesity findings;3-component Met S3,4-component Met S4,and all-component Met S5.All patients underwent complete eye examination and spectral OCT retinal imaging.RESULTS:Totally 58 eyes of 58 patients were included in the Met S group and 63 eyes of 63 age and sex-matched healthy subjects were included in CG.Met S group was composed of 22 subjects in Met S3,21 subjects in Met S4,and 15 subjects in the Met S5 subgroup.Mean foveal thickness(Met S,218.7±23.1μm vs CG,228.8±21.9μm,P=0.015),mean inferior(Met S,283.4±17.0μm vs CG,288.7±38.4μm,P=0.002),superior(Met S,287.0±18.5μm vs CG 297.3±17.1μm,P=0.001),nasal(Met S 287.3±16.7μm vs CG 297.9±13.9μm,P=0.000)and temporal(274.5±17.6μm vs CG 285.6±13.6μm,P=0.000)thickness in the 3 mm Early Treatment of Diabetic Retinopathy Study(ETDRS)circle was significantly lower in the Met S group.There was no statistically significant difference in the mean inferior,superior,nasal,and temporal thickness of 6 mm ETDRS circle,total macular volume,peripapillary and macular retinal nerve fiber layer,macular ganglion cell layer with inner plexiform layer,and ganglion cell complex.No statistically significant difference was found in these values between the Met S3,Met S4,and the Met S5 groups.CONCLUSION:A significant reduction in central macular region thickness in Met S is detected and macular thickness is more susceptible to Met S induced neurodegeneration than peripapillary retinal nerve fiber layer.
基金Supported by Grants from the Ministerio de Cienciae Innovacion,No.SAF2009-07408CIBER de Diabetesy Enfermedades Metabólicas Asociadas and Generaltitat de Catalunya,No. 2009SGR739
文摘Diabetic retinopathy(DR) has been classically considered to be a microcirculatory disease of the retina caused by the deleterious metabolic effects of hyperglycemia per se and the metabolic pathways triggered by hyperglycemia.However,retinal neurodegeneration is already present before any microcirculatory abnormalities can be detected in ophthalmoscopic examination.In other words,retinal neurodegeneration is an early event in the pathogenesis of DR which predates and participates in the microcirculatory abnormalities that occur in DR.Therefore,the study of the mechanisms that lead to neurodegeneration will be essential to identify new therapeutic targets in the early stages of DR.Elevated levels of glutamate and the overexpression of the renin-angiotensin-system play an essential role in the neurodegenerative process that occurs in diabetic retina.Among neuroprotective factors,pigment epithelial derived factor,somatostatin and erythropoietin seem to be the most relevant and these will be considered in this review.Nevertheless,it should be noted that the balance between neurotoxic and neuroprotective factors rather than levels of neurotoxic factors alone will determine the presence or absence of retinal neurodegeneration in the diabetic eye.New strategies,based on either the delivery of neuroprotective agents or the blockade of neurotoxic factors,are currently being tested in experimental models and in clinical pilot studies.Whether these novel therapies will eventually supplement or prevent the need for laser photocoagulation or vitrectomy awaits the results of additional clinical research.
基金supported in part by an award from the Soy Health Research Program(SHRP,United Soybean Board,Chesterfield,MO,USA)(to SKR)a grant(SCIRF-2015-I-01) from South Carolina Spinal Cord Injury Research Fund(Columbia,SC,USA)(to SKR)earlier R01 grants(CA-091460,and NS-057811)(to SKR) from the National Institutes of Health(Bethesda,MD,USA)
文摘All retinoids, which can be natural and synthetic, are chemically related to vitamin A. Both natural and synthetic retinoids use specific nuclear receptors such as retinoic acid receptors and retinoid X receptors to activate specific signaling pathways in the cells. Retinoic acid signaling is extremely important in the central nervous system. Impairment of retinoic acid signaling pathways causes severe pathological processes in the central nervous system, especially in the adult brain. Retinoids have major roles in neural patterning, differentiation, axon outgrowth in normal development, and function of the brain. Impaired retinoic acid signaling results in neuroinflammation, oxidative stress, mitochondrial malfunction, and neurodegeneration leading to progressive Alzheimer’s disease, which is pathologically characterized by extra-neuronal accumulation of amyloid plaques(aggregated amyloid-beta) and intra-neurofibrillary tangles(hyperphosphorylated tau protein) in the temporal lobe of the brain. Alzheimer’s disease is the most common cause of dementia and loss of memory in old adults. Inactive cholinergic neurotransmission is responsible for cognitive deficits in Alzheimer’s disease patients. Deficiency or deprivation of retinoic acid in mice is associated with loss of spatial learning and memory. Retinoids inhibit expression of chemokines and neuroinflammatory cytokines in microglia and astrocytes, which are activated in Alzheimer’s disease. Stimulation of retinoic acid receptors and retinoid X receptors slows down accumulation of amyloids, reduces neurodegeneration, and thereby prevents pathogenesis of Alzheimer’s disease in mice. In this review, we described chemistry and biochemistry of some natural and synthetic retinoids and potentials of retinoids for prevention of neuroinflammation and neurodegeneration in Alzheimer’s disease.
基金FAPERJ for the individual research fellowshipConselho Nacional de Desenvolvimento Cientifico e Tecnologico(CNPq)+2 种基金Instituto Nacional de Ciencia e Tecnologia de Neurociencia Translacional(INCT-INNT)Fundacao de Amparo a Pesquisa do Estado do Rio de Janeiro(FAPERJ)/Pensa Rio supported this workFAPERJ/CAPES for the individual scholarship
文摘Diabetes is a lifelong disease characterized by glucose metabolic imbalance,in which low insulin levels or impaired insulin signaling lead to hyperglycemic state.Within 20 years of diabetes progression,95%of patients will have diabetic retinopathy,the leading cause of visual defects in working-age people worldwide.Although diabetes is considered a microvascular disease,recent studies have shown that neurodegeneration precedes vascular changes within the diabetic visual system,albeit its mechanisms are still under investigation.Neuroinflammation and oxidative stress are intrinsically related phenomena,since macrophage/microglia and astrocytes are the main sources of reactive oxygen species during central nervous system chronic degenerative diseases,and both pathological processes are increased in the visual system during diabetes.The present review will focus on recent findings of the contribution of oxidative stress derived from neuroinflammation in the early neurodegenerative aspects of the diabetic visual system and their relationship with galectin-3.
基金American Diabetes AssociationAmerican Heart Association+3 种基金NIH NIEHSNIH NIANIH NINDSNIH ARRA
文摘Cardiovascular disease, nervous system disorders, and cancer in association with other diseases such as diabetes mellitus result in greater than sixty percent of the global annual deaths. These noncommunicable diseases also affect at least one-third of the population in low and middle-income countries and lead to hypertension, elevated cholesterol, malignancy, and neurodegenerative disorders such as Alzheimer's disease and stroke. With the climbing lifespan of the world's population, increased prevalence of these disorders is expected requiring the development of new therapeutic strategies against these disabling disease entities. Targeting stem cellproliferation for cardiac disease, vascular disorders, cancer, and neurodegenerative disorders is receiving great enthusiasm, especially those that focus upon SIRT1, a mammalian homologue of the yeast silent information regulator-2. Modulation of the cellular activity of SIRT1 can involve oversight by nicotinamide/nicotinic acid mononucleotide adenylyltransferase, mammalian forkhead transcription factors, mechanistic of rapamycin pathways, and cysteine-rich protein 61, connective tissue growth factor, and nephroblastoma over-expressed gene family members that can impact cytoprotective outcomes. Ultimately, the ability of SIRT1 to control the programmed cell death pathways of apoptosis and autophagy can determine not only cardiac, vascular, and neuronal stem cell development and longevity, but also the onset of tumorigenesis and the resistance against chemotherapy. SIRT1 therefore has a critical role and holds exciting prospects for new therapeutic strategies that can offer reparative processes for cardiac, vascular, and nervous system degenerative disorders as well as targeted control of aberrant cell growth during cancer.
基金supported by the Natural Science Foundation of Beijing of China,No.7192235(to LKX)
文摘Artemisinin,also called qinghaosu,is originally derived from the sweet wormwood plant(Artemisia annua),which is used in traditional Chinese medicine.Artemisinin and its derivatives(artemisinins)have been widely used for many years as anti-malarial agents,with few adverse side effects.Interestingly,evidence has recently shown that artemisinins might have a therapeutic value for several other diseases beyond malaria,including cancers,inflammatory diseases,and autoimmune disorders.Neurodegeneration is a challenging age-associated neurological disorder characterized by deterioration of neuronal structures as well as functions,whereas neuroinflammation has been considered to be an underlying factor in the development of various neurodegenerative disorders,including Alzheimer’s disease.Recently discovered properties of artemisinins suggested that they might be used to treat neurodegenerative disorders by decreasing oxidation,inflammation,and amyloid beta protein(Aβ).In this review,we will introduce artemisinins and highlight the possible mechanisms of their neuroprotective activities,suggesting that artemisinins might have therapeutic potential in neurodegenerative disorders.
基金supported in part by the funding from the National Institute of Allergy and Infectious Disease and the National Cancer Institute under award numbers AI138492 and CA231423 to BLH。
文摘Neuroinflammation and neurodegeneration are key components in the establishment and progression of neurodegenerative diseases including Alzheimer's Disease(AD). Over the past decade increasing evidence is emerging for the use of components of the canonical autophagy machinery in pathways that are characterized by LC3 lipidation yet are distinct from traditional macro-autophagy. One such pathway that utilizes components of the autophagy machinery to target LC3 to endosomes, a process termed LC3-associated endocytosis(LANDO), has recently been identified and regulates neuroinflammation. Abrogation of LANDO in microglia cells results in a propensity for elevated neuroinflammatory cytokine production. Using the well-established 5 xFAD model of AD to interrogate neuroinflammatory regulation, impairment of LANDO through deletion of a key upstream regulator Rubicon or other downstream autophagy components, exacerbated disease onset and severity, while deletion of microglial autophagy alone had no measurable effect. Mice presented with robust deposition of the neurotoxic AD protein β-amyloid(Aβ), microglial activation and inflammatory cytokine production, tau phosphorylation, and aggressive neurodegeneration culminating in severe memory impairment. LANDO-deficiency impaired recycling of receptors that recognize Aβ, including TLR4 and TREM2. LANDO-deficiency alone through deletion of the WD-domain of the autophagy protein ATG16 L, revealed a role for LANDO in the spontaneous establishment of age-associated AD. LANDO-deficient mice aged to 2 years presented with advanced ADlike disease and pathology correlative to that observed in human AD patients. Together, these studies illustrate an important role for microglial LANDO in regulating CNS immune activation and protection against neurodegeneration. New evidence is emerging that demonstrates a putative linkage between pathways such as LANDO and cell death regulation via apoptosis and possibly necroptosis. Herein, we provide a review of the use of the autophagy machinery in non-canonical mechanisms that alter immune regulation and could have significant impact in furthering our understanding of not only CNS diseases like AD, but likely beyond.
基金Supported by National Natural Science Foundation of China(No.81960158,No.81760176)Key Scientific research Program of Jiangxi Education Department(No.GJJ190003).
文摘●AIM:To observe the effect of inhibiting long non-coding RNA(lncRNA)metastasis-associated lung adenocarcinoma transcript 1(MALAT1)on diabetic neurodegeneration.●METHODS:Thirty-six 8-week-old C57 BL/6 mice were randomly divided into normal control,diabetic control,diabetic scrambled small interfering RNAs(siRNAs)and diabetic MALAT1-siRNA groups.After diabetic induction with streptozocin intraperitoneally-injection,the diabetic M A L AT 1-s i R N A g ro u p w a s i n t r av i t r e a l l y i n j e c te d with 1μL 20μmol/L MALAT1 siRNA,and the diabetic scrambled siRNA group was injected with the same amount of scrambled siRNA.Electroretinography was performed to examine photoreceptor functions 16 wk after diabetes induction.MALAT1 expression was detected via real time polymerase chain reaction.Cone morphological changes were examined using immunofluorescence.Rod morphological changes were examined by determining outer nuclear layer(ONL)thickness.●RESULTS:The upregulation of retinal MALAT1 expression was detected in the diabetic control mice,while MALAT1 expression in the diabetic MALAT1-siRNA mice was decreased by 91.48%compared to diabetic control mice.The diabetic MALAT1-siRNA and diabetic control mice showed lower a-wave and b-wave amplitudes than did the normal control mice in scotopic and photopic electroretinogram,while the diabetic MALAT1-siRNA mice showed higher amplitudes than diabetic control mice.Morphological examination revealed that ONL thickness in the diabetic MALAT1-siRNA and diabetic control mice was lower than normal control mice.However,ONL thickness was greater in the diabetic MALAT1-siRNA mice than diabetic control mice.Moreover,the diabetic control mice performed a sparser cone cell arrangement and shorter outer segment morphology than diabetic MALAT1-siRNA mice.●CONCLUSION:Inhibiting retinal MALAT1 results in mitigative effects on the retinal photoreceptors,thus alleviating diabetic neurodegeneration.
基金supported by the Austrian Science Fund FWF(No.P27183-B24)the Swedish Research Council Vetenskapsradet(No.2015-05468)+2 种基金Ake Wiberg Stiftelse(No.M16-0130)Carl Trygger Stiftlese(No.CTS16:85)Goljes Stiftelse(No.LA2016-0123)
文摘Cellular homeostasis requires a tightly controlled balance between protein synthesis, folding and degradation. Especially long-lived, post-mitotic cells such as neurons depend on an efficient proteostasis system to maintain cellular health over decades. Thus, a functional decline of processes contributing to protein degradation such as autophagy and general lysosomal proteolytic capacity is connected to several age-associated neurodegenerative disorders, including Parkinson's, Alzheimer's and Huntington's diseases. These so called proteinopathies are characterized by the accumulation and misfolding of distinct proteins, subsequently driving cellular demise. We recently linked efficient lysosomal protein breakdown via the protease cathepsin D to the Ca^(2+)/calmodulin-dependent phosphatase calcineurin. In a yeast model for Parkinson's disease, functional calcineurin was required for proper trafficking of cathepsin D to the lysosome and for recycling of its endosomal sorting receptor to allow further rounds of shuttling. Here, we discuss these findings in relation to present knowledge about the involvement of cathepsin D in proteinopathies in general and a possible connection between this protease, calcineurin signalling and endosomal sorting in particular. As dysregulation of Ca^(2+) homeostasis as well as lysosomal impairment is connected to a plethora of neurodegenerative disorders, this novel interplay might very well impact pathologies beyond Parkinson's disease.
基金partially supported by grants from the National Institute of Neurological Disorders and Stroke of the National Institutes of Health(R21 NS098170, to JC and CBS)Kentucky Spinal Cord and Head Injury Research Trust(16-3 A, to JC and CBS)the National Natural Science Foundation of China(81601957, to YW)。
文摘Multiple sclerosis is an autoimmune disease in which the immune system attacks the myelin sheath in the central nervous system.It is characterized by blood-brain barrier dysfunction throughout the course of multiple sclerosis, followed by the entry of immune cells and activation of local microglia and astrocytes.Glial cells(microglia, astrocytes, and oligodendrocyte lineage cells) are known as the important mediators of neuroinflammation, all of which play major roles in the pathogenesis of multiple sclerosis.Network communications between glial cells affect the activities of oligodendrocyte lineage cells and influence the demyelination-remyelination process.A finely balanced glial response may create a favorable lesion environment for efficient remyelination and neuroregeneration.This review focuses on glial response and neurodegeneration based on the findings from multiple sclerosis and major rodent demyelination models.In particular, glial interaction and molecular crosstalk are discussed to provide insights into the potential cell-and molecule-specific therapeutic targets to improve remyelination and neuroregeneration.
