BACKGROUND Hereditary spastic paraplegias (HSPs) refer to a group of heterogeneous neurodegenerative diseases characterized by lower limbs spasticity and weakness. So far, over 72 genes have been found to cause HSP (S...BACKGROUND Hereditary spastic paraplegias (HSPs) refer to a group of heterogeneous neurodegenerative diseases characterized by lower limbs spasticity and weakness. So far, over 72 genes have been found to cause HSP (SPG1-SPG72). Among autosomal dominant HSP patients, spastic paraplegia 4 (SPG4/SPAST) gene is the most common pathogenic gene, and atlastin-1 (ATL1) is the second most common one. Here we reported a novel ATL1 mutation in a Chinese spastic paraplegia 3A (SPG3A) family, which expands the clinical and genetic spectrum of ATL1 mutations. CASE SUMMARY A 9-year-old boy with progressive spastic paraplegia accompanied by right hearing loss and mental retardation for five years was admitted to our hospital.Past history was unremarkable. The family history was positive, and his grandfather and mother had similar symptoms. Neurological examinations revealed hypermyotonia in his lower limbs, hyperreflexia in knee reflex, bilateral positive Babinski signs and scissors gait. The results of blood routine test, liver function test, blood glucose test, ceruloplasmin test and vitamin test were all normal. The serum lactic acid level was significantly increased. The testing for brainstem auditory evoked potential demonstrated that the right side hearing was impaired while the left was normal. Magnetic resonance imaging showed mild atrophy of the spinal cord. The gene panel test revealed that the proband carried an ATL1 c.752A>G p.Gln251Arg (p.Q251R) mutation, and Sanger sequencing confirmed the existence of family co-segregation. CONCLUSION We reported a novel ATL1 Q251R mutation and a novel clinical phenotype of hearing loss in a Chinese SPG3A family.展开更多
SNCA,GBA,and VPS35 are three common genes associated with Parkinson's disease.Previous studies have shown that these three genes may be associated with Alzheimer's disease(AD).However,it is unclear whether the...SNCA,GBA,and VPS35 are three common genes associated with Parkinson's disease.Previous studies have shown that these three genes may be associated with Alzheimer's disease(AD).However,it is unclear whether these genes increase the risk of AD in Chinese populations.In this study,we used a targeted gene sequencing panel to screen all the exon regions and the nearby sequences of GBA,SNCA,and VPS35 in a cohort including 721 AD patients and 365 healthy controls from China.The results revealed that neither common variants nor rare variants of these three genes were associated with AD in a Chinese population.These findings suggest that the mutations in GBA,SNCA,and VPS35 are not likely to play an important role in the genetic susceptibility to AD in Chinese populations.The study was approved by the Ethics Committee of Xiangya Hospital,Central South University,China on March 9,2016(approval No.201603198).展开更多
Cerebral Amyloid Angiopathy (CAA) occurs commonly among the elderly and almost invariably in patients with Alzheimer’s Disease (AD). The β-amyloid peptides (Aβ) are produced via the amy-loidogenic processing of β-...Cerebral Amyloid Angiopathy (CAA) occurs commonly among the elderly and almost invariably in patients with Alzheimer’s Disease (AD). The β-amyloid peptides (Aβ) are produced via the amy-loidogenic processing of β-Amyloid Precursor Protein (APP) by β-secretase-1 (BACE1) and γ- secretase. Vascular endothelial cells are lately shown to possess the molecular machinery of Aβ production, which might participate in the development of CAA. Hypercholesterolemia is considered a risk factor for AD, whereas less is known if cholesterol may modulate endothelial Aβ production. In the present study we verified the amyloidogenic capability of Human Umbilical Vein Endothelial Cells (HUVECs) in vitro and explored the effect of cholesterol exposure on their amy-loidogenic potential. Cholesterol treatments at 12.5 and 25 mg/dL significantly elevated APP, BACE1 and APP β-CTF protein levels and β-site APP cleavage activity in cell lysates, and Aβ40 levels in culture medium. However, coincubation with cholesterol at 50 and 100 mg/dL attenuated the viability of the cultured cells and diminished their amyloidogenic capability. These findings suggest that high cholesterol exposure is stressful to vascular endothelial cells, and at a certain dosage range can promote an amyloidogenic response in these cells.展开更多
Exosomes are small vesicles secreted by most cell types including neurons that function in intercellular communication through transfer of their cargo or encapsulate and eliminate unnecessary cellular components and t...Exosomes are small vesicles secreted by most cell types including neurons that function in intercellular communication through transfer of their cargo or encapsulate and eliminate unnecessary cellular components and therefore have a broad impact on nerve development,activation and regeneration.In addition,exosomes have been observed to be involved in spreading pathological misfolded proteins,thereby leading to the onset and propagation of disease.Alzheimer disease(AD)is the most common form of dementia and characterized by two types of lesions:amyloid plaques and neurofibrillary tangles.Accumulating evidence has demonstrated that exosomes are associated with amyloid precursor(APP)and Tau proteins and play a controversial role in Alzheimer’s disease process.In this review,we will discuss the role of exosomes in the metabolism and secretion of APP and Tau proteins and their subsequent impact on AD pathogenesis.展开更多
Focal epilepsy accounts for 60% of all forms of epilepsy, but the pathogenic mechanism is not well understood. In this study,three novel mutations in NPRL3(nitrogen permease regulator-like 3), c.937_945del, c.1514dup ...Focal epilepsy accounts for 60% of all forms of epilepsy, but the pathogenic mechanism is not well understood. In this study,three novel mutations in NPRL3(nitrogen permease regulator-like 3), c.937_945del, c.1514dup C and 6,706-bp genomic DNA(g DNA) deletion, were identified in three families with focal epilepsy by linkage analysis, whole exome sequencing(WES) and Sanger sequencing. NPRL3 protein is a component of the GATOR1 complex, a major inhibitor of m TOR signaling. These mutations led to truncation of the NPRL3 protein and hampered the binding between NPRL3 and DEPDC5, which is another component of the GATOR1 complex. Consequently, the mutant proteins enhanced m TOR signaling in cultured cells, possibly due to impaired inhibition of m TORC1 by GATOR1. Knockdown of nprl3 in Drosophila resulted in epilepsy-like behavior and abnormal synaptic development. Taken together, these findings expand the genotypic spectrum of NPRL3-associated focal epilepsy and provide further insight into how NPRL3 mutations lead to epilepsy.展开更多
Background:Common and rare variants of guanosine triphosphate cyclohydrolase 1(GCH1)gene may play important roles in Parkinson's disease(PD).However,there is a lack of comprehensive analysis of GCH1 genotypes,espe...Background:Common and rare variants of guanosine triphosphate cyclohydrolase 1(GCH1)gene may play important roles in Parkinson's disease(PD).However,there is a lack of comprehensive analysis of GCH1 genotypes,especially in non-coding regions.The aim of this study was to explore the genetic characteristics of GCH1,including rare and common variants in coding and non-coding regions,in a large population of PD patients in Chinese mainland,as well as the phenotypic characteristics of GCH1 variant carriers.Methods:In the first cohort of this case-control study,we performed whole-exome sequencing in 1555 patients with early-onset or familial PD and 2234 healthy controls;then in the second cohort,whole-genome sequencing was performed in sporadic late-onset PD samples(1962 patients),as well as 1279 controls.Variants at target GCH1 regions were extracted,and then genetic and detailed phenotypic data were analyzed using regression models and the sequence kernel association test.We also performed a meta-analysis to correlate deleterious GCH1 variants with age at onset(AAO)in PD patients.Results:For coding variants,we identified a significant burden of GCH1 deleterious variants in early-onset or familial PD cases compared to controls(1.2%VS 0.1%,P<0.0001).In the analysis of possible regulatory variants in GCH1 non-coding regions,rs12323905(P=0.001,odds ratio=1.19,95%CI 1.07-1.32)was significantly associated with PD,and variant sets in untranslated regions and intron regions,GCH1 brain-specific expression quantitative trait loci,and two possible promoter/enhancer(GH14J054857 and GH14J054880)were suggestively associated with PD.Genotype phenotype correlation analysis revealed that the carriers of GCH1 deleterious variants manifested younger AAO(P<0.0001),and had milder motor symptoms,milder fatigue symptoms and more autonomic nervous dysfunctions.Meta-analysis of six studies demonstrated 6.4-year earlier onset in GCH1 deleterious variant carriers(P=0.0009).Conclusions:The results highlight the importance of deleterious variants and non-coding variants of GCH1 in PD in Chinese mainland and suggest that GCH1 mutation can influence the PD phenotype,which may help design experimental studies to elucidate the mechanisms of GCH1 in the pathogenesis of PD.展开更多
Background:Amyotrophic lateral sclerosis(ALS)is a devastating progressive neurodegenerative disease that affects neurons in the central nervous system and the spinal cord.As in many other neurodegenerative disorders,t...Background:Amyotrophic lateral sclerosis(ALS)is a devastating progressive neurodegenerative disease that affects neurons in the central nervous system and the spinal cord.As in many other neurodegenerative disorders,the genetic risk factors and pathogenesis of ALS involve dysregulation of cytoskeleton and neuronal transport.Notably,sen-sory and motor neuron diseases such as hereditary sensory and autonomic neuropathy type 2(HSAN2)and spastic paraplegia 30(SPG30)share several causative genes with ALS,as well as having common clinical phenotypes.KIF1A encodes a kinesin 3 motor that transports presynaptic vesicle precursors(SVPs)and dense core vesicles and has been reported as a causative gene for HSAN2 and SPG30.Methods:Here,we analyzed whole-exome sequencing data from 941 patients with ALS to investigate the genetic association of KIF1A with ALS.Results:We identified rare damage variants(RDVs)in the KIF1A gene associated with ALS and delineated the clini-cal characteristics of ALS patients with KIF1A RDVs.Clinically,these patients tended to exhibit sensory disturbance.Interestingly,the majority of these variants are located at the C-terminal cargo-binding region of the KIF1A protein.Functional examination revealed that the ALS-associated KIF1A variants located in the C-terminal region preferentially enhanced the binding of SVPs containing RAB3A,VAMP2,and synaptophysin.Expression of several disease-related KIF1A mutants in cultured mouse cortical neurons led to enhanced colocalization of RAB3A or VAMP2 with the KIF1A motor.Conclusions:Our study highlighted the importance of KIF1A motor-mediated transport in the pathogenesis of ALS,indicating KIF1A as an important player in the oligogenic scenario of ALS.展开更多
Paroxysmal dyskinesias are a group of neurological diseases characterized by intermittent episodes of involuntary movements with different causes.Paroxysmal kinesigenic dyskinesia(PKD)is the most common type of paroxy...Paroxysmal dyskinesias are a group of neurological diseases characterized by intermittent episodes of involuntary movements with different causes.Paroxysmal kinesigenic dyskinesia(PKD)is the most common type of paroxysmal dyskinesia and can be divided into primary and secondary types based on the etiology.Clinically,PKD is characterized by recurrent and transient attacks of involuntary movements precipitated by a sudden voluntary action.The major cause of primary PKD is genetic abnormalities,and the inheritance pattern of PKD is mainly autosomal-dominant with incomplete penetrance.The proline-rich transmembrane protein 2(PRRT2)was the first identified causative gene of PKD,accounting for the majority of PKD cases worldwide.An increasing number of studies has revealed the clinical and genetic characteristics,as well as the underlying mechanisms of PKD.By seeking the views of domestic experts,we propose an expert consensus regarding the diagnosis and treatment of PKD to help establish standardized clinical evaluation and therapies for PKD.In this consensus,we review the clinical manifestations,etiology,clinical diagnostic criteria and therapeutic recommendations for PKD,and results of genetic analyses in PKD patients performed in domestic hospitals.展开更多
Background:Genetic variants of dopaminergic transcription factor-encoding genes are suggested to be Parkinson’s disease(PD)risk factors;however,no comprehensive analyses of these genes in patients with PD have been u...Background:Genetic variants of dopaminergic transcription factor-encoding genes are suggested to be Parkinson’s disease(PD)risk factors;however,no comprehensive analyses of these genes in patients with PD have been undertaken.Therefore,we aimed to genetically analyze 16 dopaminergic transcription factor genes in Chinese patients with PD.Methods:Whole-exome sequencing(WES)was performed using a Chinese cohort comprising 1917 unrelated patients with familial or sporadic early-onset PD and 1652 controls.Additionally,whole-genome sequencing(WGS)was performed using another Chinese cohort comprising 1962 unrelated patients with sporadic late-onset PD and 1279 controls.Results:We detected 308 rare and 208 rare protein-altering variants in the WES and WGS cohorts,respectively.Gene-based association analyses of rare variants suggested that MSX1 is enriched in sporadic late-onset PD.However,the significance did not pass the Bonferroni correction.Meanwhile,72 and 1730 common variants were found in the WES and WGS cohorts,respectively.Unfortunately,single-variant logistic association analyses did not identify significant associations between common variants and PD.Conclusions:Variants of 16 typical dopaminergic transcription factors might not be major genetic risk factors for PD in Chinese patients.However,we highlight the complexity of PD and the need for extensive research elucidating its etiology.展开更多
Background:PINK1(PTEN-induced putative kinase 1)gene is the causal gene for recessive familial type 6 of Parkinson’s disease(PARK6),which is an early-onset autosomal recessive inherited neurodegenerative disease.PINK...Background:PINK1(PTEN-induced putative kinase 1)gene is the causal gene for recessive familial type 6 of Parkinson’s disease(PARK6),which is an early-onset autosomal recessive inherited neurodegenerative disease.PINK1 has been reported to exert both autophosphorylation and phosphorylation activity,affecting cell damage under stress and other physiological responses.However,there has been no report on the identification of PINK1 autophosphorylation sites and their physiological functions.Methods:(1)We adopted mass spectrometry assay to identify the autophosphorylation site of PINK1,and autoradiography assay was further conducted to confirm this result.(2)Kinase activity assay was used to compare the kinase activity of both Ser465 mutant PINK1 and disease-causing mutant PINK1.(3)We use Pulse-chase analysis to measure whether Ser465 may affect PINK1 degradation.(4)Immunocytochemistry staining was used to study the PINK1 subcellular localization and Parkin transition in subcellular level.Result:In our study,we identified the 465th serine residue(Ser465)as one of the autophosphorylation sites in PINK1 protein.The inactivation of Ser465 can decrease the kinase activity of PINK1.Either dissipated or excessive Ser465 site phosphorylation of PINK1 can slow down its degradation.PINK1 autophosphorylation contributes to the transit of Parkin to mitochondria,and has no effect on its subcellular localization.PARK6 causal mutations,T313 M and R492X,display the same characteristics as Ser465A mutation PINK1 protein,such as decreasing PINK1 kinase activity and affecting its interaction with Parkin.Conclusion:Ser465 was identified as one of the autophosphorylation sites of PINK1,which affected PINK1 kinase activity.In addition,Ser465 is involved in the degradation of PINK1 and the transit of Parkin to mitochondria.T313 M and R492X,two novel PARK6 mutations on Thr313 and Arg492,were similar to Ser465 mutation,including decreasing PINK1 phosphorylation activity and Parkin subcellular localization.展开更多
To the Editor:Essential tremor(ET)is a common movement disorder with significant clinical heterogeneity.[1]Following the proposal of“ET-plus”,the cross-sectional investigation of ET has increased.However,the charact...To the Editor:Essential tremor(ET)is a common movement disorder with significant clinical heterogeneity.[1]Following the proposal of“ET-plus”,the cross-sectional investigation of ET has increased.However,the characteristics of pure ET vs.ET-plus remain unclear.Herein,we present a longitudinal follow-up study of pure ET and ET-plus patients that aimed to clarify disease progression and outcome,to determine the annual incidence rates of pure ET to ET-plus,and ET to Parkinson’s disease(ETPD),and to investigate the clinical biomarkers influencing disease outcomes.展开更多
Parkinson’s disease(PD)is one of the most prevalent neurodegenerative diseases.The typical symptomatology of PD includes motor symptoms;however,a range of nonmotor symptoms,such as intestinal issues,usually occur bef...Parkinson’s disease(PD)is one of the most prevalent neurodegenerative diseases.The typical symptomatology of PD includes motor symptoms;however,a range of nonmotor symptoms,such as intestinal issues,usually occur before the motor symptoms.Various microorganisms inhabiting the gastrointestinal tract can profoundly influence the physiopathology of the central nervous system through neurological,endocrine,and immune system pathways involved in the microbiota-gut-brain axis.In addition,extensive evidence suggests that the gut microbiota is strongly associated with PD.This review summarizes the latest findings on microbial changes in PD and their clinical relevance,describes the underlying mechanisms through which intestinal bacteria may mediate PD,and discusses the correlations between gut microbes and anti-PD drugs.In addition,this review outlines the status of research on microbial therapies for PD and the future directions of PD-gut microbiota research.展开更多
Amyotrophic lateral sclerosis(ALS)is a fatal neurodegenerative disease characterized by progressive degeneration of motor neurons,and it demonstrates high clinical heterogeneity and complex genetic architecture.A vari...Amyotrophic lateral sclerosis(ALS)is a fatal neurodegenerative disease characterized by progressive degeneration of motor neurons,and it demonstrates high clinical heterogeneity and complex genetic architecture.A variation within TRMT2B(c.1356G>T;p.K452N)was identified to be associated with ALS in a family comprising two patients with juvenile ALS(JALS).Two missense variations and one splicing variation were identified in 10 patients with ALS in a cohort with 910 patients with ALS,and three more variants were identified in a public ALS database including 3317 patients with ALS.A decreased number of mitochondria,swollen mitochondria,lower expression of ND1,decreased mitochondrial complex I activities,lower mitochondrial aerobic respiration,and a high level of ROS were observed functionally in patient-originated lymphoblastoid cell lines and TRMT2B interfering HEK293 cells.Further,TRMT2B variations overexpression cells also displayed decreased ND1.In conclusion,a novel JALS-associated gene called TRMT2B was identified,thus broadening the clinical and genetic spectrum of ALS.展开更多
Background:The TANK-Binding Kinase 1(TBK1)gene has recently been identified as the third or fourth most frequent cause of frontotemporal dementia(FTD)and amyotrophic lateral sclerosis(ALS).The aim of this study was to...Background:The TANK-Binding Kinase 1(TBK1)gene has recently been identified as the third or fourth most frequent cause of frontotemporal dementia(FTD)and amyotrophic lateral sclerosis(ALS).The aim of this study was to assess the genetic contribution of TBK1 in a Chinese cohort.Methods:A total of 270 cases with ALS,FTD,or their combination were recruited into this study.All the coding exons of TBK1 and intron-exon boundaries were sequenced using Sanger sequencing.The frequency of TBK1 variants and the correlation with clinical phenotypes were analyzed.Results:A novel mutation(c.1959_1960insGT,p.E653fs)was identified in a sporadic case with semantic dementia,secondarily developing ALS.Another novel variant(c.2063_2064delTT,p.L688Rfs*14)was found in an ALS-FTD family.Totally,the TBK1 variants could only account for 0.7%of cases.Conclusions:This study enlarges the genetic and phenotypic spectrum of TBK1 mutation in a Chinese cohort.Our data indicates that TBK1 mutation is not a common cause for ALS and FTD in Chinese patients.展开更多
Parkinson’s disease(PD)is the second most common neurodegenerative disease.The development of PD is closely linked to genetic and environmental factors,with GBA1 variants being the most common genetic risk.Mutations ...Parkinson’s disease(PD)is the second most common neurodegenerative disease.The development of PD is closely linked to genetic and environmental factors,with GBA1 variants being the most common genetic risk.Mutations in the GBA1 gene lead to reduced activity of the coded enzyme,glucocerebrosidase,which mediates the development of PD by affecting lipid metabolism(especially sphingolipids),lysosomal autophagy,endoplasmic reticulum,as well as mitochondrial and other cellular functions.Clinically,PD with GBA1 mutations(GBA1-PD)is characterized by particular features regarding the progression of symptom severity.On the therapeutic side,the discovery of the relationship between GBA1 variants and PD offers an opportunity for targeted therapeutic interventions.In this review,we explore the genotypic and phenotypic correlations,etiologic mechanisms,biomarkers,and therapeutic approaches of GBA1-PD and summarize the current state of research and its challenges.展开更多
Multiple system atrophy(MSA)is a fatal progressive neurodegenerative disease.Biomarkers are urgently required for MSA to improve the diagnostic and prognostic accuracy in clinic and facilitate the development and moni...Multiple system atrophy(MSA)is a fatal progressive neurodegenerative disease.Biomarkers are urgently required for MSA to improve the diagnostic and prognostic accuracy in clinic and facilitate the development and monitoring of disease-modifying therapies.In recent years,significant research efforts have been made in exploring multidimensional biomarkers for MSA.However,currently few biomarkers are available in clinic.In this review,we systematically summarize the latest advances in multidimensional biomarkers for MSA,including biomarkers in fluids,tissues and gut microbiota as well as imaging biomarkers.Future directions for exploration of novel biomarkers and promotion of implementation in clinic are also discussed.展开更多
基金Supported by National Natural Science Foundation of China,No.81171068
文摘BACKGROUND Hereditary spastic paraplegias (HSPs) refer to a group of heterogeneous neurodegenerative diseases characterized by lower limbs spasticity and weakness. So far, over 72 genes have been found to cause HSP (SPG1-SPG72). Among autosomal dominant HSP patients, spastic paraplegia 4 (SPG4/SPAST) gene is the most common pathogenic gene, and atlastin-1 (ATL1) is the second most common one. Here we reported a novel ATL1 mutation in a Chinese spastic paraplegia 3A (SPG3A) family, which expands the clinical and genetic spectrum of ATL1 mutations. CASE SUMMARY A 9-year-old boy with progressive spastic paraplegia accompanied by right hearing loss and mental retardation for five years was admitted to our hospital.Past history was unremarkable. The family history was positive, and his grandfather and mother had similar symptoms. Neurological examinations revealed hypermyotonia in his lower limbs, hyperreflexia in knee reflex, bilateral positive Babinski signs and scissors gait. The results of blood routine test, liver function test, blood glucose test, ceruloplasmin test and vitamin test were all normal. The serum lactic acid level was significantly increased. The testing for brainstem auditory evoked potential demonstrated that the right side hearing was impaired while the left was normal. Magnetic resonance imaging showed mild atrophy of the spinal cord. The gene panel test revealed that the proband carried an ATL1 c.752A>G p.Gln251Arg (p.Q251R) mutation, and Sanger sequencing confirmed the existence of family co-segregation. CONCLUSION We reported a novel ATL1 Q251R mutation and a novel clinical phenotype of hearing loss in a Chinese SPG3A family.
基金supported by the National Natural Science Foundation of China,Nos.81971029 (to LS) and 82071216 (to BJ)。
文摘SNCA,GBA,and VPS35 are three common genes associated with Parkinson's disease.Previous studies have shown that these three genes may be associated with Alzheimer's disease(AD).However,it is unclear whether these genes increase the risk of AD in Chinese populations.In this study,we used a targeted gene sequencing panel to screen all the exon regions and the nearby sequences of GBA,SNCA,and VPS35 in a cohort including 721 AD patients and 365 healthy controls from China.The results revealed that neither common variants nor rare variants of these three genes were associated with AD in a Chinese population.These findings suggest that the mutations in GBA,SNCA,and VPS35 are not likely to play an important role in the genetic susceptibility to AD in Chinese populations.The study was approved by the Ethics Committee of Xiangya Hospital,Central South University,China on March 9,2016(approval No.201603198).
文摘Cerebral Amyloid Angiopathy (CAA) occurs commonly among the elderly and almost invariably in patients with Alzheimer’s Disease (AD). The β-amyloid peptides (Aβ) are produced via the amy-loidogenic processing of β-Amyloid Precursor Protein (APP) by β-secretase-1 (BACE1) and γ- secretase. Vascular endothelial cells are lately shown to possess the molecular machinery of Aβ production, which might participate in the development of CAA. Hypercholesterolemia is considered a risk factor for AD, whereas less is known if cholesterol may modulate endothelial Aβ production. In the present study we verified the amyloidogenic capability of Human Umbilical Vein Endothelial Cells (HUVECs) in vitro and explored the effect of cholesterol exposure on their amy-loidogenic potential. Cholesterol treatments at 12.5 and 25 mg/dL significantly elevated APP, BACE1 and APP β-CTF protein levels and β-site APP cleavage activity in cell lysates, and Aβ40 levels in culture medium. However, coincubation with cholesterol at 50 and 100 mg/dL attenuated the viability of the cultured cells and diminished their amyloidogenic capability. These findings suggest that high cholesterol exposure is stressful to vascular endothelial cells, and at a certain dosage range can promote an amyloidogenic response in these cells.
基金This study was supported through the National Natural Science Foundation of China(No.8167051815 to Lu Shen).
文摘Exosomes are small vesicles secreted by most cell types including neurons that function in intercellular communication through transfer of their cargo or encapsulate and eliminate unnecessary cellular components and therefore have a broad impact on nerve development,activation and regeneration.In addition,exosomes have been observed to be involved in spreading pathological misfolded proteins,thereby leading to the onset and propagation of disease.Alzheimer disease(AD)is the most common form of dementia and characterized by two types of lesions:amyloid plaques and neurofibrillary tangles.Accumulating evidence has demonstrated that exosomes are associated with amyloid precursor(APP)and Tau proteins and play a controversial role in Alzheimer’s disease process.In this review,we will discuss the role of exosomes in the metabolism and secretion of APP and Tau proteins and their subsequent impact on AD pathogenesis.
基金supported by the National Natural Science Foundation of China (32270663, 31871262, U20A20355,32022035)Shanghai Municipal Science and Technology Major Project(2018SHZDZX05)the Ministry of Science and Technology of China STI2030-Major Projects (2021ZD0203202)。
文摘Focal epilepsy accounts for 60% of all forms of epilepsy, but the pathogenic mechanism is not well understood. In this study,three novel mutations in NPRL3(nitrogen permease regulator-like 3), c.937_945del, c.1514dup C and 6,706-bp genomic DNA(g DNA) deletion, were identified in three families with focal epilepsy by linkage analysis, whole exome sequencing(WES) and Sanger sequencing. NPRL3 protein is a component of the GATOR1 complex, a major inhibitor of m TOR signaling. These mutations led to truncation of the NPRL3 protein and hampered the binding between NPRL3 and DEPDC5, which is another component of the GATOR1 complex. Consequently, the mutant proteins enhanced m TOR signaling in cultured cells, possibly due to impaired inhibition of m TORC1 by GATOR1. Knockdown of nprl3 in Drosophila resulted in epilepsy-like behavior and abnormal synaptic development. Taken together, these findings expand the genotypic spectrum of NPRL3-associated focal epilepsy and provide further insight into how NPRL3 mutations lead to epilepsy.
基金This study was supported by the National Key Research and Development Program of China(2016YFC1306000,2017YFC0909100,2018YFC1312000,and 2016YFC1306501)to GJ.F,T.B.S and Y.X.X,the Central Public-Interest Scientific Institution Basal Research Fund of Chinese Academy of Medical Sciences(2018-12 M-HL-025)+3 种基金to GJ.F,the National Natural Science Foundation of China(81873785,81974202)to GJ.F and T.B.S,and Science and Technology Major Project of Hunan Provincial Science and Technology Department(2018SK1030)to GJ.F,the innovative team program from Department of Sci-ence&Technology of Hunan Province(2019RS1010)to GJ.F,and the Innovation-driven Team Project from Central South University(2020CX016)to GJ.F.
文摘Background:Common and rare variants of guanosine triphosphate cyclohydrolase 1(GCH1)gene may play important roles in Parkinson's disease(PD).However,there is a lack of comprehensive analysis of GCH1 genotypes,especially in non-coding regions.The aim of this study was to explore the genetic characteristics of GCH1,including rare and common variants in coding and non-coding regions,in a large population of PD patients in Chinese mainland,as well as the phenotypic characteristics of GCH1 variant carriers.Methods:In the first cohort of this case-control study,we performed whole-exome sequencing in 1555 patients with early-onset or familial PD and 2234 healthy controls;then in the second cohort,whole-genome sequencing was performed in sporadic late-onset PD samples(1962 patients),as well as 1279 controls.Variants at target GCH1 regions were extracted,and then genetic and detailed phenotypic data were analyzed using regression models and the sequence kernel association test.We also performed a meta-analysis to correlate deleterious GCH1 variants with age at onset(AAO)in PD patients.Results:For coding variants,we identified a significant burden of GCH1 deleterious variants in early-onset or familial PD cases compared to controls(1.2%VS 0.1%,P<0.0001).In the analysis of possible regulatory variants in GCH1 non-coding regions,rs12323905(P=0.001,odds ratio=1.19,95%CI 1.07-1.32)was significantly associated with PD,and variant sets in untranslated regions and intron regions,GCH1 brain-specific expression quantitative trait loci,and two possible promoter/enhancer(GH14J054857 and GH14J054880)were suggestively associated with PD.Genotype phenotype correlation analysis revealed that the carriers of GCH1 deleterious variants manifested younger AAO(P<0.0001),and had milder motor symptoms,milder fatigue symptoms and more autonomic nervous dysfunctions.Meta-analysis of six studies demonstrated 6.4-year earlier onset in GCH1 deleterious variant carriers(P=0.0009).Conclusions:The results highlight the importance of deleterious variants and non-coding variants of GCH1 in PD in Chinese mainland and suggest that GCH1 mutation can influence the PD phenotype,which may help design experimental studies to elucidate the mechanisms of GCH1 in the pathogenesis of PD.
基金the National Key R&D Program of China(2021YFA0805200)the National Major Projects in Brain Science and Brain-like Research(2021ZD0201803 to J.W.)+7 种基金the National Natural Science Foundation of China(82171431,81671120,81300981 to J.W.,31872778 and 82171506 to Z.H.)the National Key Research and Development Program of China(#2018YFC1312003 to J.W.)the Natural Science Fund for Distinguished Young Scholars of Hunan Province,China(2020JJ2057 to J.W.)the Project Program of National Clinical Research Center for Geriatric Disorders at Xiangya Hospital(2020LNJJ13 to J.W.)Key Research and Development Programs from Hunan Province(2021DK2001 to Z.H.)the Innovative Team Program from Hunan Province(2019RS1010)the Innovation-driven Team Project from Central South University(2020CX016)the Discipline Innovative Engineering Plan(111 Program)of China(B13036).Z.H.is supported by the Hunan Hundred Talents Program for Young Outstanding Scientists.
文摘Background:Amyotrophic lateral sclerosis(ALS)is a devastating progressive neurodegenerative disease that affects neurons in the central nervous system and the spinal cord.As in many other neurodegenerative disorders,the genetic risk factors and pathogenesis of ALS involve dysregulation of cytoskeleton and neuronal transport.Notably,sen-sory and motor neuron diseases such as hereditary sensory and autonomic neuropathy type 2(HSAN2)and spastic paraplegia 30(SPG30)share several causative genes with ALS,as well as having common clinical phenotypes.KIF1A encodes a kinesin 3 motor that transports presynaptic vesicle precursors(SVPs)and dense core vesicles and has been reported as a causative gene for HSAN2 and SPG30.Methods:Here,we analyzed whole-exome sequencing data from 941 patients with ALS to investigate the genetic association of KIF1A with ALS.Results:We identified rare damage variants(RDVs)in the KIF1A gene associated with ALS and delineated the clini-cal characteristics of ALS patients with KIF1A RDVs.Clinically,these patients tended to exhibit sensory disturbance.Interestingly,the majority of these variants are located at the C-terminal cargo-binding region of the KIF1A protein.Functional examination revealed that the ALS-associated KIF1A variants located in the C-terminal region preferentially enhanced the binding of SVPs containing RAB3A,VAMP2,and synaptophysin.Expression of several disease-related KIF1A mutants in cultured mouse cortical neurons led to enhanced colocalization of RAB3A or VAMP2 with the KIF1A motor.Conclusions:Our study highlighted the importance of KIF1A motor-mediated transport in the pathogenesis of ALS,indicating KIF1A as an important player in the oligogenic scenario of ALS.
文摘Paroxysmal dyskinesias are a group of neurological diseases characterized by intermittent episodes of involuntary movements with different causes.Paroxysmal kinesigenic dyskinesia(PKD)is the most common type of paroxysmal dyskinesia and can be divided into primary and secondary types based on the etiology.Clinically,PKD is characterized by recurrent and transient attacks of involuntary movements precipitated by a sudden voluntary action.The major cause of primary PKD is genetic abnormalities,and the inheritance pattern of PKD is mainly autosomal-dominant with incomplete penetrance.The proline-rich transmembrane protein 2(PRRT2)was the first identified causative gene of PKD,accounting for the majority of PKD cases worldwide.An increasing number of studies has revealed the clinical and genetic characteristics,as well as the underlying mechanisms of PKD.By seeking the views of domestic experts,we propose an expert consensus regarding the diagnosis and treatment of PKD to help establish standardized clinical evaluation and therapies for PKD.In this consensus,we review the clinical manifestations,etiology,clinical diagnostic criteria and therapeutic recommendations for PKD,and results of genetic analyses in PKD patients performed in domestic hospitals.
基金supported by grants from the National Natural Science Foundation of China(Nos.82071437,U20A20355,and 82101342)the Hunan Innovative Province Construction Project(No.2019SK2335)+2 种基金the Natural Science Foundations of Hunan Province(No.2021JJ31115)the National Key Research and Development Program of China(Nos.2016YFC1306000 and 2021YFC2502100)the Project Program of National Clinical Research Center for Geriatric Disorders(Xiangya Hospital)(No.2021KFJJ10)
文摘Background:Genetic variants of dopaminergic transcription factor-encoding genes are suggested to be Parkinson’s disease(PD)risk factors;however,no comprehensive analyses of these genes in patients with PD have been undertaken.Therefore,we aimed to genetically analyze 16 dopaminergic transcription factor genes in Chinese patients with PD.Methods:Whole-exome sequencing(WES)was performed using a Chinese cohort comprising 1917 unrelated patients with familial or sporadic early-onset PD and 1652 controls.Additionally,whole-genome sequencing(WGS)was performed using another Chinese cohort comprising 1962 unrelated patients with sporadic late-onset PD and 1279 controls.Results:We detected 308 rare and 208 rare protein-altering variants in the WES and WGS cohorts,respectively.Gene-based association analyses of rare variants suggested that MSX1 is enriched in sporadic late-onset PD.However,the significance did not pass the Bonferroni correction.Meanwhile,72 and 1730 common variants were found in the WES and WGS cohorts,respectively.Unfortunately,single-variant logistic association analyses did not identify significant associations between common variants and PD.Conclusions:Variants of 16 typical dopaminergic transcription factors might not be major genetic risk factors for PD in Chinese patients.However,we highlight the complexity of PD and the need for extensive research elucidating its etiology.
基金This work was supported by grant 2016YFC1306000,2017YFC0909100 from the national key plan for scientific research and development of Chinagrants 81430023,81371405,81571248 from the National Natural Science Foundation of Chinagrant 2016CX025 from innovation-driven plan of Central South University,grant 2017JJ1037 from Hunan Science Funds for Distinguished Young Scholar.
文摘Background:PINK1(PTEN-induced putative kinase 1)gene is the causal gene for recessive familial type 6 of Parkinson’s disease(PARK6),which is an early-onset autosomal recessive inherited neurodegenerative disease.PINK1 has been reported to exert both autophosphorylation and phosphorylation activity,affecting cell damage under stress and other physiological responses.However,there has been no report on the identification of PINK1 autophosphorylation sites and their physiological functions.Methods:(1)We adopted mass spectrometry assay to identify the autophosphorylation site of PINK1,and autoradiography assay was further conducted to confirm this result.(2)Kinase activity assay was used to compare the kinase activity of both Ser465 mutant PINK1 and disease-causing mutant PINK1.(3)We use Pulse-chase analysis to measure whether Ser465 may affect PINK1 degradation.(4)Immunocytochemistry staining was used to study the PINK1 subcellular localization and Parkin transition in subcellular level.Result:In our study,we identified the 465th serine residue(Ser465)as one of the autophosphorylation sites in PINK1 protein.The inactivation of Ser465 can decrease the kinase activity of PINK1.Either dissipated or excessive Ser465 site phosphorylation of PINK1 can slow down its degradation.PINK1 autophosphorylation contributes to the transit of Parkin to mitochondria,and has no effect on its subcellular localization.PARK6 causal mutations,T313 M and R492X,display the same characteristics as Ser465A mutation PINK1 protein,such as decreasing PINK1 kinase activity and affecting its interaction with Parkin.Conclusion:Ser465 was identified as one of the autophosphorylation sites of PINK1,which affected PINK1 kinase activity.In addition,Ser465 is involved in the degradation of PINK1 and the transit of Parkin to mitochondria.T313 M and R492X,two novel PARK6 mutations on Thr313 and Arg492,were similar to Ser465 mutation,including decreasing PINK1 phosphorylation activity and Parkin subcellular localization.
基金supported by grants from the National Natural Science Foundation of China(Nos.U20A20355,82171256,and 82202051)the Hunan Natural Science Foundation of China(No.2021SK53501).
文摘To the Editor:Essential tremor(ET)is a common movement disorder with significant clinical heterogeneity.[1]Following the proposal of“ET-plus”,the cross-sectional investigation of ET has increased.However,the characteristics of pure ET vs.ET-plus remain unclear.Herein,we present a longitudinal follow-up study of pure ET and ET-plus patients that aimed to clarify disease progression and outcome,to determine the annual incidence rates of pure ET to ET-plus,and ET to Parkinson’s disease(ETPD),and to investigate the clinical biomarkers influencing disease outcomes.
基金supported by the National Key Plan for Scientific Research and Development of China(2021YFC2501204)the National Natural Science Foun-dation of China(81873785,82071439,81974202,and U20A20355)+2 种基金Technol-ogy Major Project of Hunan Provincial Science and Technology Department(2021SK1010)the Innovation-driven Team Project from Central South Univer-sity(2020CX016)the Innovative Team Program from the Department of Science&Technology of Hunan Province(2019RS1010).
文摘Parkinson’s disease(PD)is one of the most prevalent neurodegenerative diseases.The typical symptomatology of PD includes motor symptoms;however,a range of nonmotor symptoms,such as intestinal issues,usually occur before the motor symptoms.Various microorganisms inhabiting the gastrointestinal tract can profoundly influence the physiopathology of the central nervous system through neurological,endocrine,and immune system pathways involved in the microbiota-gut-brain axis.In addition,extensive evidence suggests that the gut microbiota is strongly associated with PD.This review summarizes the latest findings on microbial changes in PD and their clinical relevance,describes the underlying mechanisms through which intestinal bacteria may mediate PD,and discusses the correlations between gut microbes and anti-PD drugs.In addition,this review outlines the status of research on microbial therapies for PD and the future directions of PD-gut microbiota research.
基金supported by the Program of the National Natural Science Foundation of China(Nos.82171431 and 31972886)the Natural Science Fund for Distinguished Young Scholars of Hunan Province,China(Nos.2020JJ2057 and 2021JJ10074)+6 种基金Natural Science Foundation of Changsha City(No.kq2208402)the Program of the National Natural Science Foundation of Hunan Province(No.2021JJ40989)the Project Program of National Clinical Research Center for Geriatric Disorders at Xiangya Hospital(No.2020LNJJ13)the Science and Technology Innovation 2030(STI2030-Major Projects,No.2021ZD0201803)the National Key R&D Program of China(No.2021YFA0805202)the Innovation Team Project of Hunan Province(No.2019RS1010)the Innovation Team Project of Central South University(No.2020CX016).
文摘Amyotrophic lateral sclerosis(ALS)is a fatal neurodegenerative disease characterized by progressive degeneration of motor neurons,and it demonstrates high clinical heterogeneity and complex genetic architecture.A variation within TRMT2B(c.1356G>T;p.K452N)was identified to be associated with ALS in a family comprising two patients with juvenile ALS(JALS).Two missense variations and one splicing variation were identified in 10 patients with ALS in a cohort with 910 patients with ALS,and three more variants were identified in a public ALS database including 3317 patients with ALS.A decreased number of mitochondria,swollen mitochondria,lower expression of ND1,decreased mitochondrial complex I activities,lower mitochondrial aerobic respiration,and a high level of ROS were observed functionally in patient-originated lymphoblastoid cell lines and TRMT2B interfering HEK293 cells.Further,TRMT2B variations overexpression cells also displayed decreased ND1.In conclusion,a novel JALS-associated gene called TRMT2B was identified,thus broadening the clinical and genetic spectrum of ALS.
基金supported by the National Natural Science Foundation of China(No.81471295 and No.81671075 to Lu Shen,No.81701134 to Bin Jiao)the National Key Plan for Scientific Research and Development of China(No.2016YFC1306000 to Beisha Tang)the Xiangya Hospital Youth Scientific Research Fund(No.2016Q01 to Bin Jiao).
文摘Background:The TANK-Binding Kinase 1(TBK1)gene has recently been identified as the third or fourth most frequent cause of frontotemporal dementia(FTD)and amyotrophic lateral sclerosis(ALS).The aim of this study was to assess the genetic contribution of TBK1 in a Chinese cohort.Methods:A total of 270 cases with ALS,FTD,or their combination were recruited into this study.All the coding exons of TBK1 and intron-exon boundaries were sequenced using Sanger sequencing.The frequency of TBK1 variants and the correlation with clinical phenotypes were analyzed.Results:A novel mutation(c.1959_1960insGT,p.E653fs)was identified in a sporadic case with semantic dementia,secondarily developing ALS.Another novel variant(c.2063_2064delTT,p.L688Rfs*14)was found in an ALS-FTD family.Totally,the TBK1 variants could only account for 0.7%of cases.Conclusions:This study enlarges the genetic and phenotypic spectrum of TBK1 mutation in a Chinese cohort.Our data indicates that TBK1 mutation is not a common cause for ALS and FTD in Chinese patients.
基金supported by the National Key Plan for Scientific Research and Development of China(2021YFC2501204)the National Key R&D Program of China(2021YFC2502100)+3 种基金the National Natural Science Foundation of China(81873785,82071439,81974202,U20A20355)Technology Major Project of Hunan Provincial Science and Technology Department(2021SK1010)the Innovation-driven Team Project from Central South University(2020CX016)the Innovative Team Program from the Department of Science&Technology of Hunan Province(2019RS1010).
文摘Parkinson’s disease(PD)is the second most common neurodegenerative disease.The development of PD is closely linked to genetic and environmental factors,with GBA1 variants being the most common genetic risk.Mutations in the GBA1 gene lead to reduced activity of the coded enzyme,glucocerebrosidase,which mediates the development of PD by affecting lipid metabolism(especially sphingolipids),lysosomal autophagy,endoplasmic reticulum,as well as mitochondrial and other cellular functions.Clinically,PD with GBA1 mutations(GBA1-PD)is characterized by particular features regarding the progression of symptom severity.On the therapeutic side,the discovery of the relationship between GBA1 variants and PD offers an opportunity for targeted therapeutic interventions.In this review,we explore the genotypic and phenotypic correlations,etiologic mechanisms,biomarkers,and therapeutic approaches of GBA1-PD and summarize the current state of research and its challenges.
基金funded by the National Key R&D Program of China(2021YFA0805200 to H Jiang)the National Natural Science Foundation of China(81974176 and 82171254 to H Jiang)+6 种基金the Innovation Research Group Project of Natural Science Foundation of Hunan Province(2020JJ1008 to H Jiang)the Scientific Research Foundation of Health Commission of Hunan Province(B2019183 to H Jiang)the Key Research and Development Program of Hunan Province(2020SK2064 to H Jiang)the Innovative Research and Development Program of Development and Reform Commission of Hunan Province to H Jiang,the Natural Science Foundation of Hunan Province(2022JJ20094 and 2021JJ40974 to Z Chen)the Central South University Research Programme of Advanced Interdisciplinary Study(2023QYJC010 to H Jiang)the Project Program of National Clinical Research Center for Geriatric Disorders,Xiangya Hospital(2020LNJJ12 to H Jiang)the Science and Technology Innovation Program of Hunan Province(2022RC1027 to Z Chen).
文摘Multiple system atrophy(MSA)is a fatal progressive neurodegenerative disease.Biomarkers are urgently required for MSA to improve the diagnostic and prognostic accuracy in clinic and facilitate the development and monitoring of disease-modifying therapies.In recent years,significant research efforts have been made in exploring multidimensional biomarkers for MSA.However,currently few biomarkers are available in clinic.In this review,we systematically summarize the latest advances in multidimensional biomarkers for MSA,including biomarkers in fluids,tissues and gut microbiota as well as imaging biomarkers.Future directions for exploration of novel biomarkers and promotion of implementation in clinic are also discussed.
