Huntington’s disease is a neurodegenerative disease caused by the expansion mutation of a cytosine-adenine-guanine triplet in the exon 1 of the HTT gene which is responsible for the production of the huntingtin (Htt)...Huntington’s disease is a neurodegenerative disease caused by the expansion mutation of a cytosine-adenine-guanine triplet in the exon 1 of the HTT gene which is responsible for the production of the huntingtin (Htt) protein. In physiological conditions, Htt is involved in many cellular processes such as cell signaling, transcriptional regulation, energy metabolism regulation, DNA maintenance, axonal trafficking, and antiapoptotic activity. When the genetic alteration is present, the production of a mutant version of Htt (mHtt) occurs, which is characterized by a plethora of pathogenic activities that, finally, lead to cell death. Among all the cells in which mHtt exerts its dangerous activity, the GABAergic Medium Spiny Neurons seem to be the most affected by the mHtt-induced excitotoxicity both in the cortex and in the striatum. However, as the neurodegeneration proceeds ahead the neuronal loss grows also in other brain areas such as the cerebellum, hypothalamus, thalamus, subthalamic nucleus, globus pallidus, and substantia nigra, determining the variety of symptoms that characterize Huntington’s disease. From a clinical point of view, Huntington’s disease is characterized by a wide spectrum of symptoms spanning from motor impairment to cognitive disorders and dementia. Huntington’s disease shows a prevalence of around 3.92 cases every 100,000 worldwide and an incidence of 0.48 new cases every 100,000/year. To date, there is no available cure for Huntington’s disease. Several treatments have been developed so far, aiming to reduce the severity of one or more symptoms to slow down the inexorable decline caused by the disease. In this context, the search for reliable strategies to target the different aspects of Huntington’s disease become of the utmost interest. In recent years, a variety of studies demonstrated the detrimental role of neuronal loss in Huntington’s disease condition highlighting how the replacement of lost cells would be a reasonable strategy to overcome the neurodegeneration. In this view, numerous have been the attempts in several preclinical models of Huntington’s disease to evaluate the feasibility of invasive and non-invasive approaches. Thus, the aim of this review is to offer an overview of the most appealing approaches spanning from stem cell-based cell therapy to extracellular vesicles such as exosomes in light of promoting neurogenesis, discussing the results obtained so far, their limits and the future perspectives regarding the neural regeneration in the context of Huntington’s disease.展开更多
Neurotrophic factors,or neurotrophins,are a group of molecules supporting the growth,survival,and differentiation of developing and mature neurons.Given their role in the survival of neurons,and often of specific subs...Neurotrophic factors,or neurotrophins,are a group of molecules supporting the growth,survival,and differentiation of developing and mature neurons.Given their role in the survival of neurons,and often of specific subsets of brain cells,neurotrophins have been implicated in several ways with many neurodegenerative disorders.展开更多
Huntington’s disease(HD)is a genetic disease characterized by the progressive degeneration of the striatum and cortex.Patients can present with a variety of symptoms that can broadly be classified into motor symptoms...Huntington’s disease(HD)is a genetic disease characterized by the progressive degeneration of the striatum and cortex.Patients can present with a variety of symptoms that can broadly be classified into motor symptoms,inclusive of choreatic movements and rigidity,mood and psychiatric symptoms,such as depression and apathy,and cognitive symptoms,such as cognitive decline.The causal mutation underlying HD results from an expansion of a CAG repeat sequence on the IT15 gene,resulting in the formation and accumulation of a mutant huntingtin protein.展开更多
Huntington’s disease is a genetic disease caused by expanded CAG repeats on exon 1 of the huntingtin gene located on chromosome 4.Compelling evidence implicates impaired mitochondrial energetics,altered mitochondrial...Huntington’s disease is a genetic disease caused by expanded CAG repeats on exon 1 of the huntingtin gene located on chromosome 4.Compelling evidence implicates impaired mitochondrial energetics,altered mitochondrial biogenesis and quality control,disturbed mitochondrial trafficking,oxidative stress and mitochondrial calcium dyshomeostasis in the pathogenesis of the disorder.Unfortunately,conventional mitochondrial-targeted molecules,such as cysteamine,creatine,coenzyme Q10,or triheptanoin,yielded negative or inconclusive results.However,future therapeutic strategies,aiming to restore mitochondrial biogenesis,improving the fission/fusion balance,and improving mitochondrial trafficking,could prove useful tools in improving the phenotype of Huntington’s disease and,used in combination with genome-editing methods,could lead to a cure for the disease.展开更多
The renin-angiotensin system(RAS)was originally conceived as a circulating hormonal system involved in the regulation of cardiovascular and renal homeostasis.With the discovery of local RAS components in diverse organ...The renin-angiotensin system(RAS)was originally conceived as a circulating hormonal system involved in the regulation of cardiovascular and renal homeostasis.With the discovery of local RAS components in diverse organs,including the brain,and related biologically active peptides.展开更多
On February 16,a new study published in the journal of Nature Biomedical Engineering demonstrated the potential of CRISPR/Cas9 technology to combat Huntington’s disease(HD),a devastating neurodegenerative disorder.
A review of recent animal models of Huntington’s disease showed many microRNAs had altered expression levels in the striatum and cerebral cortex,and which were mostly downregulated.Among the altered microRNAs were mi...A review of recent animal models of Huntington’s disease showed many microRNAs had altered expression levels in the striatum and cerebral cortex,and which were mostly downregulated.Among the altered microRNAs were miR-9/9*,miR-29b,miR-124a,miR-132,miR-128,miR-139,miR-122,miR-138,miR-23b,miR-135b,miR-181(all downregulated)and miR-448(upregulated),and similar changes had been previously found in Huntington’s disease patients.In the animal cell studies,the altered microRNAs included miR-9,miR-9*,miR-135b,miR-222(all downregulated)and miR-214(upregulated).In the animal models,overexpression of miR-155 and miR-196a caused a decrease in mutant huntingtin mRNA and protein level,lowered the mutant huntingtin aggregates in striatum and cortex,and improved performance in behavioral tests.Improved performance in behavioral tests also occurred with overexpression of miR-132 and miR-124.In the animal cell models,overexpression of miR-22 increased the viability of rat primary cortical and striatal neurons infected with mutant huntingtin and decreased huntingtin-enriched foci of≥2μm.Also,overexpression of miR-22 enhanced the survival of rat primary striatal neurons treated with 3-nitropropionic acid.Exogenous expression of miR-214,miR-146a,miR-150,and miR-125b decreased endogenous expression of huntingtin mRNA and protein in HdhQ111/HdhQ111 cells.Further studies with animal models of Huntington’s disease are warranted to validate these findings and identify specific microRNAs whose overexpression inhibits the production of mutant huntingtin protein and other harmful processes and may provide a more effective means of treating Huntington’s disease in patients and slowing its progression.展开更多
Huntington’s disease(HD)is a genetic neurodegenerative disorder that affects not only the motor but also the cognitive domain.In particular,cognitive symptoms such as impaired executive skills and deficits in recogni...Huntington’s disease(HD)is a genetic neurodegenerative disorder that affects not only the motor but also the cognitive domain.In particular,cognitive symptoms such as impaired executive skills and deficits in recognizing other individuals’mental state may emerge many years before the motor symptoms.This study was aimed at testing two cognitive hypotheses suggested by previous research with a new Stroop task created for the purpose:1)the impairment of emotion recognition in HD is moderated by the emotions’valence,and 2)inhibitory control is impaired in HD.Forty manifest and 20 pre-manifest HD patients and their age-and gender-matched controls completed both the traditional“Stroop Color and Word Test”(SCWT)and the newly created“Stroop Emotion Recognition under Word Interference Task”(SERWIT),which consist in 120 photographs of sad,calm,or happy faces with either congruent or incongruent word interference.On the SERWIT,impaired emotion recognition in manifest HD was moderated by emotion type,with deficits being larger in recognizing sadness and calmness than in recognizing happiness,but it was not moderated by stimulus congruency.On the SCWT,six different interference scores yielded as many different patterns of group effects.Overall our results corroborate the hypothesis that impaired emotion recognition in HD is moderated by the emotions’valence,but do not provide evidence for the hypothesis that inhibitory control is impaired in HD.Further research is needed to learn more about the psychological mechanisms underlying the moderating effect of emotional valence on impaired emotion recognition in HD,and to corroborate the hypothesis that the inhibitory processes involved in Stroop tasks are not impaired in HD.Looking beyond this study,the SERWIT promises to make important contributions to disentangling the cognitive and the psychomotor aspects of neurological disorders.The research was approved by the Ethics Committee of the“Istituto Leonarda Vaccari”,Rome on January 24,2018.展开更多
Objective Linguistic problem is common in Huntington’s disease(HD)patients.It has been studied before in native speakers of alphabetic languages,such as English.As a hieroglyphic language,Chinese differs from alphabe...Objective Linguistic problem is common in Huntington’s disease(HD)patients.It has been studied before in native speakers of alphabetic languages,such as English.As a hieroglyphic language,Chinese differs from alphabetic languages in terms of phonology,morphology,semantics and syntax.We aimed to investigate the linguistic characteristics of manifest HD in native speakers of Mandarin.Meanwhile,we expected to explore the linguistic differences associated with cortical or subcortical pathology.Methods Five HD patients and five Alzheimer’s disease(AD)patients matched in age,gender,disease course and educational level were enrolled.All the participants were Mandarin native speakers.All finished history inquiry,physical examination,basic test,genetic test and neuropsychological assessment.Language evaluation was performed by Aphasia Battery of Chinese.Results HD patients had a mean disease course of 5.4±2.97(range,2-10)years.They showed a linguistic disorder close to transcortical motor aphasia.They exhibited prominent phonological impairment,as well as slight semantic and syntactic abnormality.Tonic errors were found in speech.Character structural errors and substitutions were detected in writing.In comparison,AD patients showed a more severe linguistic impairment,characterized by global aphasia with more semantic errors.Conclusion Mandarin-speaking HD patients have a transcortical motor aphasia-like disturbance with prominent phonological impairment,whereas AD patients have a more severe global aphasia with salient semantic impairment.展开更多
Although relatively rare, Huntington’s disease (HD) has fatal consequences. There is no cure for the disease, which leads to an early death. Worldwide, scientists are trying to develop therapeutic methods that could ...Although relatively rare, Huntington’s disease (HD) has fatal consequences. There is no cure for the disease, which leads to an early death. Worldwide, scientists are trying to develop therapeutic methods that could cure the disease, including new molecular gene therapeutic methods. At Lund University, research on HD is now about to step from animal models to trials with humans. The project is special in its design since it involves both medical studies and socio-cultural and psychological research to explore and meet the many challenges that experimental trials with HD patients give rise to. The aim of the present study was to investigate the viewpoints of individuals affected by HD on the issues of participation and exerting influence if taking part in a medical study on gene therapy that has not previously been tested on humans. A total of 16 participants, recruited through the national association for HD and through the neurological clinic at Lund University in Sweden, took part in a focus group or in a survey study. A thematic analysis, to explore the transcribed text from the focus groups as well as from the written mail responses, was conducted by means of Nvivo, a program for qualitative data analysis. Results showed three main themes expressing reasons for participation: participation as a last resort, as an activity of hope, and as a way to take responsibility for the development of a cure that will benefit future generations. The responses relating to the question about affected individuals’ view of exerting influence resulted in two themes. The first theme was having a voice when researchers design experiments, which may give a sense of receiving respect. The second was that influence is an essential part of the information process before agreeing to take part in an experimental trail.展开更多
Huntington’s disease(HD)is an irreversible neurodegenerative disorder that is inherited in an autosomal dominant manner.In HD,many regions of the human brain are affected,including the striatum,thalamus,and cortex.Th...Huntington’s disease(HD)is an irreversible neurodegenerative disorder that is inherited in an autosomal dominant manner.In HD,many regions of the human brain are affected,including the striatum,thalamus,and cortex.The mechanism is by the expansion of CAG repeats,which encode glutamine(Q)in the Huntingtin gene on chromosome 4p16.3.Patients with more CAG repeats tend to have a younger age of onset and a higher risk.Mutant HTT protein,translated from mtHtt,would congregate or interact with other proteins,causing damage to the human body.Patients with HD show symptoms like chorea,which is an involuntary motor disability,cognitive deterioration,and psychiatric disturbances.Except for the genetic pathology of HD,the epigenetic mechanism of this disease has made a lot of progress in recent years.This paper primarily focuses on the alternation of deoxyribonucleic acid(DNA)methylation,histone modification,and non-coding ribonucleic acids(ncRNAs)in HD as well as the advancements of epigenetic therapy and healthcare in HD.展开更多
This study investigated episodic memory in prodromal HD. Three groups were compared (N = 70): mutation carriers with less than 12.5 years to disease onset (n = 16), mutation carriers with 12.5 or more years to disease...This study investigated episodic memory in prodromal HD. Three groups were compared (N = 70): mutation carriers with less than 12.5 years to disease onset (n = 16), mutation carriers with 12.5 or more years to disease onset (n = 16), and noncarriers (n = 38). Episodic memory was assessed using the Fuld Object Memory Evaluation, which included multimodal presentation and selective reminding, and the Claeson-Dahl Learning Test which included verbal repeated presentation and recall trials. Both carrier groups demonstrated deficient episodic memory compared to noncarriers. The results suggest deficient episodic memory in prodromal HD, and that inconsistent retrieval contributes to these deficits. Multimodal presentation attenuates the deficits.展开更多
Heat shock factor 1(HSF1)is abnormally degraded in Huntington’s disease(HD):HD is a neurodegenerative disorder characterized by severe cognitive and motor impairments.HD is caused by a CAG repeat expansion within exo...Heat shock factor 1(HSF1)is abnormally degraded in Huntington’s disease(HD):HD is a neurodegenerative disorder characterized by severe cognitive and motor impairments.HD is caused by a CAG repeat expansion within exon 1 of the huntingtin(HTT)gene(The Huntington’s Disease Collaborative Research Group,1993).These expansions lead to the production of an aberrant mutant huntingtin protein(mHTT)that is prone to misfolding and aggregation.Expression and aggregation of mHTT is present in virtually all cell types in the body but preferentially affects medium spiny neurons of the striatum,a brain region that controls movement and some forms of cognition.Accumulation of mHTT leads to,but not only,transcriptional dysregulation,DNA damage,mitochondrial dysfunction and excitatory synaptic failure ultimately causing neuronal death.However,the molecular mechanisms by which mHTT exerts these defects are still unclear.展开更多
In 1872, George Huntington presented his essay “On Chorea” to the Meigs and Mason Academy of Medicine and, in doing so, detailed a disease that would later bear his name. Huntington's disease(HD) is a genetic, n...In 1872, George Huntington presented his essay “On Chorea” to the Meigs and Mason Academy of Medicine and, in doing so, detailed a disease that would later bear his name. Huntington's disease(HD) is a genetic, neurodegenerative disease that manifests as the loss of motor control,cognitive impairment,and mood and psychiatric changes in paents.展开更多
Brain-derived neurotrophic factor(BDNF)exerts pleiotropic effects on brain processes including psychiatric disorders,aging,neurodegeneration,and metabolic homeostasis.A simple PubMed search using the key word“BDNF,”...Brain-derived neurotrophic factor(BDNF)exerts pleiotropic effects on brain processes including psychiatric disorders,aging,neurodegeneration,and metabolic homeostasis.A simple PubMed search using the key word“BDNF,”to date,yields over 33,000 publications.From fundamental biology to potential therapeutic applications,BDNF has clearly garnered extensive and significant attention in the field of neurobiology research.展开更多
Neurological disorders are a diverse group of conditions that affect the nervous system and include neurodegenerative diseases(Alzheimer’s disease,multiple sclerosis,Parkinson’s disease,Huntington’s disease),cerebr...Neurological disorders are a diverse group of conditions that affect the nervous system and include neurodegenerative diseases(Alzheimer’s disease,multiple sclerosis,Parkinson’s disease,Huntington’s disease),cerebrovascular conditions(stroke),and neurodevelopmental disorders(autism spectrum disorder).Although they affect millions of individuals around the world,only a limited number of effective treatment options are available today.Since most neurological disorders express mitochondria-related metabolic perturbations,metformin,a biguanide type II antidiabetic drug,has attracted a lot of attention to be repurposed to treat neurological disorders by correcting their perturbed energy metabolism.However,controversial research emerges regarding the beneficial/detrimental effects of metformin on these neurological disorders.Given that most neurological disorders have complex etiology in their pathophysiology and are influenced by various risk factors such as aging,lifestyle,genetics,and environment,it is important to identify perturbed molecular functions that can be targeted by metformin in these neurological disorders.These molecules can then be used as biomarkers to stratify subpopulations of patients who show distinct molecular/pathological properties and can respond to metformin treatment,ultimately developing targeted therapy.In this review,we will discuss mitochondria-related metabolic perturbations and impaired molecular pathways in these neurological disorders and how these can be used as biomarkers to guide metformin-responsive treatment for the targeted therapy to treat neurological disorders.展开更多
Exosomes are cup-shaped extracellular vesicles with a lipid bilayer that is approximately 30 to 200 nm in thickness.Exosomes are widely distributed in a range of body fluids,including urine,blood,milk,and saliva.Exoso...Exosomes are cup-shaped extracellular vesicles with a lipid bilayer that is approximately 30 to 200 nm in thickness.Exosomes are widely distributed in a range of body fluids,including urine,blood,milk,and saliva.Exosomes exert biological function by transporting factors between different cells and by regulating biological pathways in recipient cells.As an important form of intercellular communication,exosomes are increasingly being investigated due to their ability to transfer bioactive molecules such as lipids,proteins,mRNAs,and microRNAs between cells,and because they can regulate physiological and pathological processes in the central nervous system.Adult neurogenesis is a multistage process by which new neurons are generated and migrate to be integrated into existing neuronal circuits.In the adult brain,neurogenesis is mainly localized in two specialized niches:the subventricular zone adjacent to the lateral ventricles and the subgranular zone of the dentate gyrus.An increasing body of evidence indicates that adult neurogenesis is tightly controlled by environmental conditions with the niches.In recent studies,exosomes released from different sources of cells were shown to play an active role in regulating neurogenesis both in vitro and in vivo,thereby participating in the progression of neurodegenerative disorders in patients and in various disease models.Here,we provide a state-of-the-art synopsis of existing research that aimed to identify the diverse components of exosome cargoes and elucidate the therapeutic potential of exosomal contents in the regulation of neurogenesis in several neurodegenerative diseases.We emphasize that exosomal cargoes could serve as a potential biomarker to monitor functional neurogenesis in adults.In addition,exosomes can also be considered as a novel therapeutic approach to treat various neurodegenerative disorders by improving endogenous neurogenesis to mitigate neuronal loss in the central nervous system.展开更多
Neurodegenerative diseases are a group of disorders characterized by the progressive degeneration of neurons in the central or peripheral nervous system.Currently,there is no cure for neurodegenerative diseases and th...Neurodegenerative diseases are a group of disorders characterized by the progressive degeneration of neurons in the central or peripheral nervous system.Currently,there is no cure for neurodegenerative diseases and this means a heavy burden for patients and the health system worldwide.Therefore,it is necessary to find new therapeutic approaches,and antisense therapies offer this possibility,having the great advantage of not modifying cellular genome and potentially being safer.Many preclinical and clinical studies aim to test the safety and effectiveness of antisense therapies in the treatment of neurodegenerative diseases.The objective of this review is to summarize the recent advances in the development of these new technologies to treat the most common neurodegenerative diseases,with a focus on those antisense therapies that have already received the approval of the U.S.Food and Drug Administration.展开更多
文摘Huntington’s disease is a neurodegenerative disease caused by the expansion mutation of a cytosine-adenine-guanine triplet in the exon 1 of the HTT gene which is responsible for the production of the huntingtin (Htt) protein. In physiological conditions, Htt is involved in many cellular processes such as cell signaling, transcriptional regulation, energy metabolism regulation, DNA maintenance, axonal trafficking, and antiapoptotic activity. When the genetic alteration is present, the production of a mutant version of Htt (mHtt) occurs, which is characterized by a plethora of pathogenic activities that, finally, lead to cell death. Among all the cells in which mHtt exerts its dangerous activity, the GABAergic Medium Spiny Neurons seem to be the most affected by the mHtt-induced excitotoxicity both in the cortex and in the striatum. However, as the neurodegeneration proceeds ahead the neuronal loss grows also in other brain areas such as the cerebellum, hypothalamus, thalamus, subthalamic nucleus, globus pallidus, and substantia nigra, determining the variety of symptoms that characterize Huntington’s disease. From a clinical point of view, Huntington’s disease is characterized by a wide spectrum of symptoms spanning from motor impairment to cognitive disorders and dementia. Huntington’s disease shows a prevalence of around 3.92 cases every 100,000 worldwide and an incidence of 0.48 new cases every 100,000/year. To date, there is no available cure for Huntington’s disease. Several treatments have been developed so far, aiming to reduce the severity of one or more symptoms to slow down the inexorable decline caused by the disease. In this context, the search for reliable strategies to target the different aspects of Huntington’s disease become of the utmost interest. In recent years, a variety of studies demonstrated the detrimental role of neuronal loss in Huntington’s disease condition highlighting how the replacement of lost cells would be a reasonable strategy to overcome the neurodegeneration. In this view, numerous have been the attempts in several preclinical models of Huntington’s disease to evaluate the feasibility of invasive and non-invasive approaches. Thus, the aim of this review is to offer an overview of the most appealing approaches spanning from stem cell-based cell therapy to extracellular vesicles such as exosomes in light of promoting neurogenesis, discussing the results obtained so far, their limits and the future perspectives regarding the neural regeneration in the context of Huntington’s disease.
文摘Neurotrophic factors,or neurotrophins,are a group of molecules supporting the growth,survival,and differentiation of developing and mature neurons.Given their role in the survival of neurons,and often of specific subsets of brain cells,neurotrophins have been implicated in several ways with many neurodegenerative disorders.
文摘Huntington’s disease(HD)is a genetic disease characterized by the progressive degeneration of the striatum and cortex.Patients can present with a variety of symptoms that can broadly be classified into motor symptoms,inclusive of choreatic movements and rigidity,mood and psychiatric symptoms,such as depression and apathy,and cognitive symptoms,such as cognitive decline.The causal mutation underlying HD results from an expansion of a CAG repeat sequence on the IT15 gene,resulting in the formation and accumulation of a mutant huntingtin protein.
文摘Huntington’s disease is a genetic disease caused by expanded CAG repeats on exon 1 of the huntingtin gene located on chromosome 4.Compelling evidence implicates impaired mitochondrial energetics,altered mitochondrial biogenesis and quality control,disturbed mitochondrial trafficking,oxidative stress and mitochondrial calcium dyshomeostasis in the pathogenesis of the disorder.Unfortunately,conventional mitochondrial-targeted molecules,such as cysteamine,creatine,coenzyme Q10,or triheptanoin,yielded negative or inconclusive results.However,future therapeutic strategies,aiming to restore mitochondrial biogenesis,improving the fission/fusion balance,and improving mitochondrial trafficking,could prove useful tools in improving the phenotype of Huntington’s disease and,used in combination with genome-editing methods,could lead to a cure for the disease.
基金financial support from the Brazili an government funding agencies:FAPEMIG(Funda??o de AmparoàPesquisa do Estado de Minas Gerais,Brazil)CNPq(Conselho Nacional de Desenvoivimento Cientificoe Tecnologico,Brazil)+1 种基金CAPES(Coordena??o de Aperfei?oamento de Pessoal de Nivel Superior)ALT received financial support from UTHealth Department of Psychiatry and Behavioral Sciences,NIH/NIA,TARCC.ASM and ALT are CNPq fellowship recipients。
文摘The renin-angiotensin system(RAS)was originally conceived as a circulating hormonal system involved in the regulation of cardiovascular and renal homeostasis.With the discovery of local RAS components in diverse organs,including the brain,and related biologically active peptides.
文摘On February 16,a new study published in the journal of Nature Biomedical Engineering demonstrated the potential of CRISPR/Cas9 technology to combat Huntington’s disease(HD),a devastating neurodegenerative disorder.
文摘A review of recent animal models of Huntington’s disease showed many microRNAs had altered expression levels in the striatum and cerebral cortex,and which were mostly downregulated.Among the altered microRNAs were miR-9/9*,miR-29b,miR-124a,miR-132,miR-128,miR-139,miR-122,miR-138,miR-23b,miR-135b,miR-181(all downregulated)and miR-448(upregulated),and similar changes had been previously found in Huntington’s disease patients.In the animal cell studies,the altered microRNAs included miR-9,miR-9*,miR-135b,miR-222(all downregulated)and miR-214(upregulated).In the animal models,overexpression of miR-155 and miR-196a caused a decrease in mutant huntingtin mRNA and protein level,lowered the mutant huntingtin aggregates in striatum and cortex,and improved performance in behavioral tests.Improved performance in behavioral tests also occurred with overexpression of miR-132 and miR-124.In the animal cell models,overexpression of miR-22 increased the viability of rat primary cortical and striatal neurons infected with mutant huntingtin and decreased huntingtin-enriched foci of≥2μm.Also,overexpression of miR-22 enhanced the survival of rat primary striatal neurons treated with 3-nitropropionic acid.Exogenous expression of miR-214,miR-146a,miR-150,and miR-125b decreased endogenous expression of huntingtin mRNA and protein in HdhQ111/HdhQ111 cells.Further studies with animal models of Huntington’s disease are warranted to validate these findings and identify specific microRNAs whose overexpression inhibits the production of mutant huntingtin protein and other harmful processes and may provide a more effective means of treating Huntington’s disease in patients and slowing its progression.
基金“Fondazione Cattolica Assicurazione” for funding the observational research of LIRH Foundation (www. lirh.it)
文摘Huntington’s disease(HD)is a genetic neurodegenerative disorder that affects not only the motor but also the cognitive domain.In particular,cognitive symptoms such as impaired executive skills and deficits in recognizing other individuals’mental state may emerge many years before the motor symptoms.This study was aimed at testing two cognitive hypotheses suggested by previous research with a new Stroop task created for the purpose:1)the impairment of emotion recognition in HD is moderated by the emotions’valence,and 2)inhibitory control is impaired in HD.Forty manifest and 20 pre-manifest HD patients and their age-and gender-matched controls completed both the traditional“Stroop Color and Word Test”(SCWT)and the newly created“Stroop Emotion Recognition under Word Interference Task”(SERWIT),which consist in 120 photographs of sad,calm,or happy faces with either congruent or incongruent word interference.On the SERWIT,impaired emotion recognition in manifest HD was moderated by emotion type,with deficits being larger in recognizing sadness and calmness than in recognizing happiness,but it was not moderated by stimulus congruency.On the SCWT,six different interference scores yielded as many different patterns of group effects.Overall our results corroborate the hypothesis that impaired emotion recognition in HD is moderated by the emotions’valence,but do not provide evidence for the hypothesis that inhibitory control is impaired in HD.Further research is needed to learn more about the psychological mechanisms underlying the moderating effect of emotional valence on impaired emotion recognition in HD,and to corroborate the hypothesis that the inhibitory processes involved in Stroop tasks are not impaired in HD.Looking beyond this study,the SERWIT promises to make important contributions to disentangling the cognitive and the psychomotor aspects of neurological disorders.The research was approved by the Ethics Committee of the“Istituto Leonarda Vaccari”,Rome on January 24,2018.
基金supported by grants from CAMS Innovation Fund for Medical Sciences(No.2016-I2M-1-004)National Natural Science Foundation of China(No.81550021)+1 种基金13th Five-year National Key Research and Development Program of China(No.2016YFC1306300)the strategic priority research program(pilot study)“Biological basis of aging and therapeutic strategies”of the Chinese Academy of Sciences(XDPB10)。
文摘Objective Linguistic problem is common in Huntington’s disease(HD)patients.It has been studied before in native speakers of alphabetic languages,such as English.As a hieroglyphic language,Chinese differs from alphabetic languages in terms of phonology,morphology,semantics and syntax.We aimed to investigate the linguistic characteristics of manifest HD in native speakers of Mandarin.Meanwhile,we expected to explore the linguistic differences associated with cortical or subcortical pathology.Methods Five HD patients and five Alzheimer’s disease(AD)patients matched in age,gender,disease course and educational level were enrolled.All the participants were Mandarin native speakers.All finished history inquiry,physical examination,basic test,genetic test and neuropsychological assessment.Language evaluation was performed by Aphasia Battery of Chinese.Results HD patients had a mean disease course of 5.4±2.97(range,2-10)years.They showed a linguistic disorder close to transcortical motor aphasia.They exhibited prominent phonological impairment,as well as slight semantic and syntactic abnormality.Tonic errors were found in speech.Character structural errors and substitutions were detected in writing.In comparison,AD patients showed a more severe linguistic impairment,characterized by global aphasia with more semantic errors.Conclusion Mandarin-speaking HD patients have a transcortical motor aphasia-like disturbance with prominent phonological impairment,whereas AD patients have a more severe global aphasia with salient semantic impairment.
文摘Although relatively rare, Huntington’s disease (HD) has fatal consequences. There is no cure for the disease, which leads to an early death. Worldwide, scientists are trying to develop therapeutic methods that could cure the disease, including new molecular gene therapeutic methods. At Lund University, research on HD is now about to step from animal models to trials with humans. The project is special in its design since it involves both medical studies and socio-cultural and psychological research to explore and meet the many challenges that experimental trials with HD patients give rise to. The aim of the present study was to investigate the viewpoints of individuals affected by HD on the issues of participation and exerting influence if taking part in a medical study on gene therapy that has not previously been tested on humans. A total of 16 participants, recruited through the national association for HD and through the neurological clinic at Lund University in Sweden, took part in a focus group or in a survey study. A thematic analysis, to explore the transcribed text from the focus groups as well as from the written mail responses, was conducted by means of Nvivo, a program for qualitative data analysis. Results showed three main themes expressing reasons for participation: participation as a last resort, as an activity of hope, and as a way to take responsibility for the development of a cure that will benefit future generations. The responses relating to the question about affected individuals’ view of exerting influence resulted in two themes. The first theme was having a voice when researchers design experiments, which may give a sense of receiving respect. The second was that influence is an essential part of the information process before agreeing to take part in an experimental trail.
文摘Huntington’s disease(HD)is an irreversible neurodegenerative disorder that is inherited in an autosomal dominant manner.In HD,many regions of the human brain are affected,including the striatum,thalamus,and cortex.The mechanism is by the expansion of CAG repeats,which encode glutamine(Q)in the Huntingtin gene on chromosome 4p16.3.Patients with more CAG repeats tend to have a younger age of onset and a higher risk.Mutant HTT protein,translated from mtHtt,would congregate or interact with other proteins,causing damage to the human body.Patients with HD show symptoms like chorea,which is an involuntary motor disability,cognitive deterioration,and psychiatric disturbances.Except for the genetic pathology of HD,the epigenetic mechanism of this disease has made a lot of progress in recent years.This paper primarily focuses on the alternation of deoxyribonucleic acid(DNA)methylation,histone modification,and non-coding ribonucleic acids(ncRNAs)in HD as well as the advancements of epigenetic therapy and healthcare in HD.
基金Department of Clinical Genetics, Karolinska University Hospital
文摘This study investigated episodic memory in prodromal HD. Three groups were compared (N = 70): mutation carriers with less than 12.5 years to disease onset (n = 16), mutation carriers with 12.5 or more years to disease onset (n = 16), and noncarriers (n = 38). Episodic memory was assessed using the Fuld Object Memory Evaluation, which included multimodal presentation and selective reminding, and the Claeson-Dahl Learning Test which included verbal repeated presentation and recall trials. Both carrier groups demonstrated deficient episodic memory compared to noncarriers. The results suggest deficient episodic memory in prodromal HD, and that inconsistent retrieval contributes to these deficits. Multimodal presentation attenuates the deficits.
文摘Heat shock factor 1(HSF1)is abnormally degraded in Huntington’s disease(HD):HD is a neurodegenerative disorder characterized by severe cognitive and motor impairments.HD is caused by a CAG repeat expansion within exon 1 of the huntingtin(HTT)gene(The Huntington’s Disease Collaborative Research Group,1993).These expansions lead to the production of an aberrant mutant huntingtin protein(mHTT)that is prone to misfolding and aggregation.Expression and aggregation of mHTT is present in virtually all cell types in the body but preferentially affects medium spiny neurons of the striatum,a brain region that controls movement and some forms of cognition.Accumulation of mHTT leads to,but not only,transcriptional dysregulation,DNA damage,mitochondrial dysfunction and excitatory synaptic failure ultimately causing neuronal death.However,the molecular mechanisms by which mHTT exerts these defects are still unclear.
文摘In 1872, George Huntington presented his essay “On Chorea” to the Meigs and Mason Academy of Medicine and, in doing so, detailed a disease that would later bear his name. Huntington's disease(HD) is a genetic, neurodegenerative disease that manifests as the loss of motor control,cognitive impairment,and mood and psychiatric changes in paents.
文摘Brain-derived neurotrophic factor(BDNF)exerts pleiotropic effects on brain processes including psychiatric disorders,aging,neurodegeneration,and metabolic homeostasis.A simple PubMed search using the key word“BDNF,”to date,yields over 33,000 publications.From fundamental biology to potential therapeutic applications,BDNF has clearly garnered extensive and significant attention in the field of neurobiology research.
文摘Neurological disorders are a diverse group of conditions that affect the nervous system and include neurodegenerative diseases(Alzheimer’s disease,multiple sclerosis,Parkinson’s disease,Huntington’s disease),cerebrovascular conditions(stroke),and neurodevelopmental disorders(autism spectrum disorder).Although they affect millions of individuals around the world,only a limited number of effective treatment options are available today.Since most neurological disorders express mitochondria-related metabolic perturbations,metformin,a biguanide type II antidiabetic drug,has attracted a lot of attention to be repurposed to treat neurological disorders by correcting their perturbed energy metabolism.However,controversial research emerges regarding the beneficial/detrimental effects of metformin on these neurological disorders.Given that most neurological disorders have complex etiology in their pathophysiology and are influenced by various risk factors such as aging,lifestyle,genetics,and environment,it is important to identify perturbed molecular functions that can be targeted by metformin in these neurological disorders.These molecules can then be used as biomarkers to stratify subpopulations of patients who show distinct molecular/pathological properties and can respond to metformin treatment,ultimately developing targeted therapy.In this review,we will discuss mitochondria-related metabolic perturbations and impaired molecular pathways in these neurological disorders and how these can be used as biomarkers to guide metformin-responsive treatment for the targeted therapy to treat neurological disorders.
基金supported by grants from the Department of Science and Technology of Sichuan Province,Nos.2021ZYD0093(to LY),2022YFS0597(to LY),2021YJ0480(to YT),and 2022ZYD0076(to JY)。
文摘Exosomes are cup-shaped extracellular vesicles with a lipid bilayer that is approximately 30 to 200 nm in thickness.Exosomes are widely distributed in a range of body fluids,including urine,blood,milk,and saliva.Exosomes exert biological function by transporting factors between different cells and by regulating biological pathways in recipient cells.As an important form of intercellular communication,exosomes are increasingly being investigated due to their ability to transfer bioactive molecules such as lipids,proteins,mRNAs,and microRNAs between cells,and because they can regulate physiological and pathological processes in the central nervous system.Adult neurogenesis is a multistage process by which new neurons are generated and migrate to be integrated into existing neuronal circuits.In the adult brain,neurogenesis is mainly localized in two specialized niches:the subventricular zone adjacent to the lateral ventricles and the subgranular zone of the dentate gyrus.An increasing body of evidence indicates that adult neurogenesis is tightly controlled by environmental conditions with the niches.In recent studies,exosomes released from different sources of cells were shown to play an active role in regulating neurogenesis both in vitro and in vivo,thereby participating in the progression of neurodegenerative disorders in patients and in various disease models.Here,we provide a state-of-the-art synopsis of existing research that aimed to identify the diverse components of exosome cargoes and elucidate the therapeutic potential of exosomal contents in the regulation of neurogenesis in several neurodegenerative diseases.We emphasize that exosomal cargoes could serve as a potential biomarker to monitor functional neurogenesis in adults.In addition,exosomes can also be considered as a novel therapeutic approach to treat various neurodegenerative disorders by improving endogenous neurogenesis to mitigate neuronal loss in the central nervous system.
基金supported by Association 2HE(Center for Human Health and Environment)by Regione Puglia-Grant Malattie Rare DUP n.246 of 2019(to CB).
文摘Neurodegenerative diseases are a group of disorders characterized by the progressive degeneration of neurons in the central or peripheral nervous system.Currently,there is no cure for neurodegenerative diseases and this means a heavy burden for patients and the health system worldwide.Therefore,it is necessary to find new therapeutic approaches,and antisense therapies offer this possibility,having the great advantage of not modifying cellular genome and potentially being safer.Many preclinical and clinical studies aim to test the safety and effectiveness of antisense therapies in the treatment of neurodegenerative diseases.The objective of this review is to summarize the recent advances in the development of these new technologies to treat the most common neurodegenerative diseases,with a focus on those antisense therapies that have already received the approval of the U.S.Food and Drug Administration.
