A previous study of European Caucasian patients with sporadic amyotrophic lateral sclerosis demonstrated that a polymorphism in the microtubule-associated protein Tau （MAPT） gene was significantly associated with sp...A previous study of European Caucasian patients with sporadic amyotrophic lateral sclerosis demonstrated that a polymorphism in the microtubule-associated protein Tau （MAPT） gene was significantly associated with sporadic amyotrophic lateral sclerosis pathogenesis. Here, we tested this association in 107 sporadic amyotrophic lateral sclerosis patients and 100 healthy controls from the Chinese Han population. We screened the mutation-susceptible regions of MAPT- the 3＇ and 5＇ untranslated regions as well as introns 9, 10, 11, and 12 - by direct sequencing, and identified 33 genetic variations. Two of these, 105788 A 〉 G in intron 9 and 123972 T 〉 A in intron 11, were not present in the control group. The age of onset in patients with the 105788 A 〉 G and/or the 123972 T 〉 A variant was younger than that in patients without either genetic variation. Moreover, the pa- tients with a genetic variation were more prone to bulbar palsy and breathing difficulties than those with the wild-type genotype. This led to a shorter survival period in patients with a MAPT genetic variant. Our study suggests that the MAPT gene is a potential risk gene for sporadic amyotrophic lateral sclerosis in the Chinese Han population.展开更多
目的:报道1例微管相关蛋白-tau(microtubule-associated protein tau,MAPT)基因突变所致行为变异型额颞叶痴呆家系患者的临床表现、神经系统查体、家系图、神经心理学检测、头颅磁共振表现及基因检查特征,并进行文献复习。方法:收集行...目的:报道1例微管相关蛋白-tau(microtubule-associated protein tau,MAPT)基因突变所致行为变异型额颞叶痴呆家系患者的临床表现、神经系统查体、家系图、神经心理学检测、头颅磁共振表现及基因检查特征,并进行文献复习。方法:收集行为变异型额颞叶痴呆(behavioral variant frontotemporal dementia,bvFTD)患者1例,进行询问病史、神经系统查体和神经心理学检查,并行常规化验、头颅磁共振表现及基因检查,并复习相关文献。结果:该例患者表现为突出的性格改变、行为异常下降,症状进行性加重,家族中两人有类似临床症状。患者头颅MRI提示双侧颞前极和顶叶对称性脑萎缩,海马萎缩较轻。基因检查提示MAPT基因c.915+16C>T杂合突变。报道bvFTD以社会行为异常、性格改变和认知功能持续性下降为主要表现,是FTLD中遗传性最强的亚型,MAPT基因是其最常见的致病基因之一。结论:本例bvFTD患者存在MAPT基因c.915+16C>T杂合突变,从而引发神经变性。对于临床诊断bvFTD的患者应完善基因学检测。展开更多
Alzheimer’s disease(AD),the most common neurodegenerative disorder,is characterized by memory loss and cognitive dysfunction.The accumulation of misfolded protein aggregates including amyloid beta(Aβ)peptides and mi...Alzheimer’s disease(AD),the most common neurodegenerative disorder,is characterized by memory loss and cognitive dysfunction.The accumulation of misfolded protein aggregates including amyloid beta(Aβ)peptides and microtubule associated protein tau(MAPT/tau)in neuronal cells are hallmarks of AD.So far,the exact underlying mechanisms for the aetiologies of AD have not been fully understood and the effective treatment for AD is limited.Autophagy is an evolutionarily conserved cellular catabolic process by which damaged cellular organelles and protein aggregates are degraded via lysosomes.Recently,there is accumulating evidence linking the impairment of the autophagy-lysosomal pathway with AD pathogenesis.Interestingly,the enhancement of autophagy to remove protein aggregates has been proposed as a promising therapeutic strategy for AD.Here,we first summarize the recent genetic,pathological and experimental studies regarding the impairment of the autophagy-lysosomal pathway in AD.We then describe the interplay between the autophagy-lysosomal pathway and two pathological proteins,Aβand MAPT/tau,in AD.Finally,we discuss potential therapeutic strategies and small molecules that target the autophagy-lysosomal pathway for AD treatment both in animal models and in clinical trials.Overall,this article highlights the pivotal functions of the autophagy-lysosomal pathway in AD pathogenesis and potential druggable targets in the autophagy-lysosomal pathway for AD treatment.展开更多
Frontotemporal lobar degeneration(FTLD)represents a group of clinically,neuropathologically and genetically heterogeneous disorders with plenty of overlaps between the neurodegenerative mechanism and the clinical phen...Frontotemporal lobar degeneration(FTLD)represents a group of clinically,neuropathologically and genetically heterogeneous disorders with plenty of overlaps between the neurodegenerative mechanism and the clinical phenotype.FTLD is pathologically characterized by the frontal and temporal lobar atrophy.Frontotemporal dementia(FTD)clinically presents with abnormalities of behavior and personality and language impairments variants.The clinical spectrum of FTD encompasses distinct canonical syndromes:behavioural variant of FTD(bvFTD)and primary progressive aphasia.The later includes nonfluent/agrammatic variant PPA(nfvPPA or PNFA),semantic variant PPA(svPPA or SD)and logopenic variant PPA(lvPPA).In addition,there is also overlap of FTD with motor neuron disease(FTD-MND or FTD-ALS),as well as the parkinsonian syndromes,progressive supranuclear palsy(PSP)and corticobasal syndrome(CBS).The FTLD spectrum disorders are based upon the predominant neuropathological proteins(containing inclusions of hyperphosphorylated tau or ubiquitin protein,e.g transactive response(TAR)DNA-binding protein 43 kDa(TDP-43)and fusedin-sarcoma protein in neurons and glial cells)into three main categories:(1)microtubule-associated protein tau(FTLD-Tau);(2)TAR DNA-binding protein-43(FTLD-TDP);and(3)fused in sarcoma protein(FTLD-FUS).There are five main genes mutations leading clinical and pathological variants in FTLD that identified by molecular genetic studies,which are chromosome 9 open reading frame 72(C9ORF72)gene,granulin(GRN)gene,microtubule associated protein tau gene(MAPT),the gene encoding valosin-containing protein(VCP)and the charged multivesicular body protein 2B(CHMP2B).In this review,recent advances on the different clinic variants,neuroimaging,genetics,pathological subtypes and clinicopathological associations of FTD will be discussed.展开更多
基金funded by the National Natural Science Foundation of China,No.30560042 and 81260194Jiangxi Provincial Health Bureau of Science and Technology Program,No.20111028
文摘A previous study of European Caucasian patients with sporadic amyotrophic lateral sclerosis demonstrated that a polymorphism in the microtubule-associated protein Tau （MAPT） gene was significantly associated with sporadic amyotrophic lateral sclerosis pathogenesis. Here, we tested this association in 107 sporadic amyotrophic lateral sclerosis patients and 100 healthy controls from the Chinese Han population. We screened the mutation-susceptible regions of MAPT- the 3＇ and 5＇ untranslated regions as well as introns 9, 10, 11, and 12 - by direct sequencing, and identified 33 genetic variations. Two of these, 105788 A 〉 G in intron 9 and 123972 T 〉 A in intron 11, were not present in the control group. The age of onset in patients with the 105788 A 〉 G and/or the 123972 T 〉 A variant was younger than that in patients without either genetic variation. Moreover, the pa- tients with a genetic variation were more prone to bulbar palsy and breathing difficulties than those with the wild-type genotype. This led to a shorter survival period in patients with a MAPT genetic variant. Our study suggests that the MAPT gene is a potential risk gene for sporadic amyotrophic lateral sclerosis in the Chinese Han population.
基金funding supports from the National Natural Science Foundation of China(82003721,82071193,32170774 and 32000673)Shenzhen Science and Technology Innovation Commission(JCYJ20210324114014039,China)+1 种基金China Postdoctoral Science Foundation(2020M683182)Guangdong Basic and Applied Basic Research Foundation(2020A1515110549,China)。
文摘Alzheimer’s disease(AD),the most common neurodegenerative disorder,is characterized by memory loss and cognitive dysfunction.The accumulation of misfolded protein aggregates including amyloid beta(Aβ)peptides and microtubule associated protein tau(MAPT/tau)in neuronal cells are hallmarks of AD.So far,the exact underlying mechanisms for the aetiologies of AD have not been fully understood and the effective treatment for AD is limited.Autophagy is an evolutionarily conserved cellular catabolic process by which damaged cellular organelles and protein aggregates are degraded via lysosomes.Recently,there is accumulating evidence linking the impairment of the autophagy-lysosomal pathway with AD pathogenesis.Interestingly,the enhancement of autophagy to remove protein aggregates has been proposed as a promising therapeutic strategy for AD.Here,we first summarize the recent genetic,pathological and experimental studies regarding the impairment of the autophagy-lysosomal pathway in AD.We then describe the interplay between the autophagy-lysosomal pathway and two pathological proteins,Aβand MAPT/tau,in AD.Finally,we discuss potential therapeutic strategies and small molecules that target the autophagy-lysosomal pathway for AD treatment both in animal models and in clinical trials.Overall,this article highlights the pivotal functions of the autophagy-lysosomal pathway in AD pathogenesis and potential druggable targets in the autophagy-lysosomal pathway for AD treatment.
基金This work was supported by the grants from the National Natural Science Foundation of China(81200991)Outstanding Young Persons’Research Program for Higher Education of Fujian Province,China(JA10123)Major Project of Fujian Science and Technology Bureau(2009D061).
文摘Frontotemporal lobar degeneration(FTLD)represents a group of clinically,neuropathologically and genetically heterogeneous disorders with plenty of overlaps between the neurodegenerative mechanism and the clinical phenotype.FTLD is pathologically characterized by the frontal and temporal lobar atrophy.Frontotemporal dementia(FTD)clinically presents with abnormalities of behavior and personality and language impairments variants.The clinical spectrum of FTD encompasses distinct canonical syndromes:behavioural variant of FTD(bvFTD)and primary progressive aphasia.The later includes nonfluent/agrammatic variant PPA(nfvPPA or PNFA),semantic variant PPA(svPPA or SD)and logopenic variant PPA(lvPPA).In addition,there is also overlap of FTD with motor neuron disease(FTD-MND or FTD-ALS),as well as the parkinsonian syndromes,progressive supranuclear palsy(PSP)and corticobasal syndrome(CBS).The FTLD spectrum disorders are based upon the predominant neuropathological proteins(containing inclusions of hyperphosphorylated tau or ubiquitin protein,e.g transactive response(TAR)DNA-binding protein 43 kDa(TDP-43)and fusedin-sarcoma protein in neurons and glial cells)into three main categories:(1)microtubule-associated protein tau(FTLD-Tau);(2)TAR DNA-binding protein-43(FTLD-TDP);and(3)fused in sarcoma protein(FTLD-FUS).There are five main genes mutations leading clinical and pathological variants in FTLD that identified by molecular genetic studies,which are chromosome 9 open reading frame 72(C9ORF72)gene,granulin(GRN)gene,microtubule associated protein tau gene(MAPT),the gene encoding valosin-containing protein(VCP)and the charged multivesicular body protein 2B(CHMP2B).In this review,recent advances on the different clinic variants,neuroimaging,genetics,pathological subtypes and clinicopathological associations of FTD will be discussed.
