AIM:To evaluate aspects of cognition impacted by individuals with and without normal tension glaucoma.METHODS:Fifty normal tension glaucoma(NTG)and 50 control patients≥50 y of age were recruited from the UCSF Departm...AIM:To evaluate aspects of cognition impacted by individuals with and without normal tension glaucoma.METHODS:Fifty normal tension glaucoma(NTG)and 50 control patients≥50 y of age were recruited from the UCSF Department of Ophthalmology.Demographic data and glaucoma parameters were extracted from electronic medical records for both groups.Tests of executive function[Executive Abilities:Measures and Instruments for Neurobehavioral Evaluation and Research(EXAMINER)]and learning and memory[California Verbal Learning Test–Second Edition(CVLT-II)]were administered to both NTG and controls.Race,handedness,best-corrected visual acuity,maximum intraocular pressure,optic nerve cup-todisc ratio,visual field and optic nerve optical coherence tomography parameters,and a measure of general health(Charlson Comorbidity Index)were compared between NTG and controls as well as within NTG subgroups.Multivariate linear regression was used to compare group performances on the EXAMINER battery and CVLT-II while controlling for age,sex,and years of education.RESULTS:NTG and controls were comparable with respect to age,sex,race,education,handedness,and the Charlson Comorbidity Index(P>0.05 for all).Performance on the EXAMINER composite score and the CVLT-II did not differ between NTG and controls(P>0.05 for both).CONCLUSION:This is the first prospective study in which the cognitive function of subject with NTG were evaluated using a comprehensive,computerized neurocognitive battery.Subjects with NTG do not perform worse than unaffected controls on tests of executive function,learning,and memor y.Results do not suppor t the hypothesis that individuals with NTG are at higher risk for cognitive dysfunction and/or dementia.展开更多
Restless Legs Syndrome is characterized by the irresistible, often indescribable unpleasant urge to move the limbs while resting. It has an estimated prevalence of ～ 29.3 % in US private practice. Restless Legs Syndr...Restless Legs Syndrome is characterized by the irresistible, often indescribable unpleasant urge to move the limbs while resting. It has an estimated prevalence of ～ 29.3 % in US private practice. Restless Legs Syndrome often has a familial component; whether the familial and non- familial forms differ in terms of clinical features has previously been investigated, with the only significant factor emerging as younger age at onset in familial cases. Our study further explores a possible underlying difference between familial and sporadic forms of RLS by comparing familial RLS with sporadic RLS in terms of demographic and clinical features including subject gender, age of onset, and severity measures based an the IRLSSG severity scale. Both gender and family history are significant predictors of onset age in an overall model and also significant when analyzed independently. Participants who reported more severe RLS symptoms were significantly younger in age and progressed more rapidly. Two variables from the IRLSSG severity scale were significantly associated with age of onset when tested independently: discomfort and the urge to move the limb for relief. Our analysis supports the prevailing hypothesis that RLS is divided into earlier onset disease with a clear genetic component and later onset disease wich unclear etiology, and that one or more endophenotypes might exist within the disorder which could further characterize these subjects for future genetic studies.展开更多
Hypertonia is a neurological dysfunction associated with a number of central nervous system disorders, including cerebral palsy, Parkinson＇s disease, dystonia, and epilepsy. Genetic studies have identified a homozygo...Hypertonia is a neurological dysfunction associated with a number of central nervous system disorders, including cerebral palsy, Parkinson＇s disease, dystonia, and epilepsy. Genetic studies have identified a homozygous truncation mutation in Trakl that causes hypertonia in mice. Moreover, elevated Trakl protein expression is associated with several types of cancers and variants in Trakl are linked to childhood absence epilepsy in humans. Despite the importance of Trakl in health and disease, the mechanisms of Trakl action remain unclear and the pathogenic effects of Trakl mutation are unknown. Here we report that Trakl has a crucial function in regulation of mitochondrial fusion. Depletion of Trakl inhibits mitochondrial fusion, result- ing in mitochondrial fragmentation, whereas overex- pression of Trakl elongates and enlarges mitochondria. Our analyses revealed that Trakl interacts and colocal- izes with mitofusins on the outer mitochondrial mem- brane and functions with mitofusins to promote mitochondrial tethering and fusion. Furthermore, Trakl is required for stress-induced mitochondrial hyperfu- sion and pro-survival response. We found that hyper- tonia-associated mutation impairs Trakl mitochondrial localization and its ability to facilitate mitochondrial tethering and fusion. Our findings uncover a novel function of Trakl as a regulator of mitochondrial fusion and provide evidence linking dysregulated mitochon- drial dynamics to hypertonia pathogenesis.展开更多
The VCP-Ufd1-Npl4 complex regulates proteasomal processing within cells by delivering ubiquitinated proteins to the proteasome for degradation.Mutations in VCP are associated with two neurodegenerative diseases,amyotr...The VCP-Ufd1-Npl4 complex regulates proteasomal processing within cells by delivering ubiquitinated proteins to the proteasome for degradation.Mutations in VCP are associated with two neurodegenerative diseases,amyotrophic lateral sclerosis（ALS） and inclusion body myopathy with Paget＇s disease of the bone and frontotemporal dementia（IBMPFD）,and extensive study has revealed crucial functions of VCP within neurons.By contrast,little is known about the functions of Npl4 or Ufd1 in vivo.Using neuronalspecific knockdown of Npl4 or Ufd1 in Drosophila melanogaster,we infer that Npl4 contributes to microtubule organization within developing motor neurons.Moreover,Npl4 RNAi flies present with neurodegenerative phenotypes including progressive locomotor deficits,reduced lifespan and increased accumulation of TAR DNA-binding protein-43 homolog（TBPH）.Knockdown,but not overexpression,of TBPH also exacerbates Npl4 RNAi-associated adult-onset neurodegenerative phenotypes.In contrast,we find that neuronal knockdown of Ufd1 has little effect on neuromuscular junction（NMJ） organization,TBPH accumulation or adult behaviour.These findings suggest the differing neuronal functions of Npl4 and Ufd1 in vivo.展开更多
基金Supported by the Core Grant for Vision Research and the Research to Prevent Blindness Unrestricted Grant to the UCSF Department of Ophthalmology(No.NIH-NEI EY002162)。
文摘AIM:To evaluate aspects of cognition impacted by individuals with and without normal tension glaucoma.METHODS:Fifty normal tension glaucoma(NTG)and 50 control patients≥50 y of age were recruited from the UCSF Department of Ophthalmology.Demographic data and glaucoma parameters were extracted from electronic medical records for both groups.Tests of executive function[Executive Abilities:Measures and Instruments for Neurobehavioral Evaluation and Research(EXAMINER)]and learning and memory[California Verbal Learning Test–Second Edition(CVLT-II)]were administered to both NTG and controls.Race,handedness,best-corrected visual acuity,maximum intraocular pressure,optic nerve cup-todisc ratio,visual field and optic nerve optical coherence tomography parameters,and a measure of general health(Charlson Comorbidity Index)were compared between NTG and controls as well as within NTG subgroups.Multivariate linear regression was used to compare group performances on the EXAMINER battery and CVLT-II while controlling for age,sex,and years of education.RESULTS:NTG and controls were comparable with respect to age,sex,race,education,handedness,and the Charlson Comorbidity Index(P>0.05 for all).Performance on the EXAMINER composite score and the CVLT-II did not differ between NTG and controls(P>0.05 for both).CONCLUSION:This is the first prospective study in which the cognitive function of subject with NTG were evaluated using a comprehensive,computerized neurocognitive battery.Subjects with NTG do not perform worse than unaffected controls on tests of executive function,learning,and memor y.Results do not suppor t the hypothesis that individuals with NTG are at higher risk for cognitive dysfunction and/or dementia.
文摘Restless Legs Syndrome is characterized by the irresistible, often indescribable unpleasant urge to move the limbs while resting. It has an estimated prevalence of ～ 29.3 % in US private practice. Restless Legs Syndrome often has a familial component; whether the familial and non- familial forms differ in terms of clinical features has previously been investigated, with the only significant factor emerging as younger age at onset in familial cases. Our study further explores a possible underlying difference between familial and sporadic forms of RLS by comparing familial RLS with sporadic RLS in terms of demographic and clinical features including subject gender, age of onset, and severity measures based an the IRLSSG severity scale. Both gender and family history are significant predictors of onset age in an overall model and also significant when analyzed independently. Participants who reported more severe RLS symptoms were significantly younger in age and progressed more rapidly. Two variables from the IRLSSG severity scale were significantly associated with age of onset when tested independently: discomfort and the urge to move the limb for relief. Our analysis supports the prevailing hypothesis that RLS is divided into earlier onset disease with a clear genetic component and later onset disease wich unclear etiology, and that one or more endophenotypes might exist within the disorder which could further characterize these subjects for future genetic studies.
文摘Hypertonia is a neurological dysfunction associated with a number of central nervous system disorders, including cerebral palsy, Parkinson＇s disease, dystonia, and epilepsy. Genetic studies have identified a homozygous truncation mutation in Trakl that causes hypertonia in mice. Moreover, elevated Trakl protein expression is associated with several types of cancers and variants in Trakl are linked to childhood absence epilepsy in humans. Despite the importance of Trakl in health and disease, the mechanisms of Trakl action remain unclear and the pathogenic effects of Trakl mutation are unknown. Here we report that Trakl has a crucial function in regulation of mitochondrial fusion. Depletion of Trakl inhibits mitochondrial fusion, result- ing in mitochondrial fragmentation, whereas overex- pression of Trakl elongates and enlarges mitochondria. Our analyses revealed that Trakl interacts and colocal- izes with mitofusins on the outer mitochondrial mem- brane and functions with mitofusins to promote mitochondrial tethering and fusion. Furthermore, Trakl is required for stress-induced mitochondrial hyperfu- sion and pro-survival response. We found that hyper- tonia-associated mutation impairs Trakl mitochondrial localization and its ability to facilitate mitochondrial tethering and fusion. Our findings uncover a novel function of Trakl as a regulator of mitochondrial fusion and provide evidence linking dysregulated mitochon- drial dynamics to hypertonia pathogenesis.
基金supported by a Wellcome Trust-NIH PhD studentship(200927/Z/16/Z)a Wellcome Trust Vacation Studentship (WT200927)
文摘The VCP-Ufd1-Npl4 complex regulates proteasomal processing within cells by delivering ubiquitinated proteins to the proteasome for degradation.Mutations in VCP are associated with two neurodegenerative diseases,amyotrophic lateral sclerosis（ALS） and inclusion body myopathy with Paget＇s disease of the bone and frontotemporal dementia（IBMPFD）,and extensive study has revealed crucial functions of VCP within neurons.By contrast,little is known about the functions of Npl4 or Ufd1 in vivo.Using neuronalspecific knockdown of Npl4 or Ufd1 in Drosophila melanogaster,we infer that Npl4 contributes to microtubule organization within developing motor neurons.Moreover,Npl4 RNAi flies present with neurodegenerative phenotypes including progressive locomotor deficits,reduced lifespan and increased accumulation of TAR DNA-binding protein-43 homolog（TBPH）.Knockdown,but not overexpression,of TBPH also exacerbates Npl4 RNAi-associated adult-onset neurodegenerative phenotypes.In contrast,we find that neuronal knockdown of Ufd1 has little effect on neuromuscular junction（NMJ） organization,TBPH accumulation or adult behaviour.These findings suggest the differing neuronal functions of Npl4 and Ufd1 in vivo.
