This study reports a case of a 75-year-old female Machado-Joseph disease patient exhibiting unstable walking and inaccurate hand holding for 8 months, which progressively worsened. Physical examination on admission sh...This study reports a case of a 75-year-old female Machado-Joseph disease patient exhibiting unstable walking and inaccurate hand holding for 8 months, which progressively worsened. Physical examination on admission showed cerebellar ataxia and a history of hypertension. Crania MRI demonstrated cerebellar and brain stem atrophy. Gene analysis showed abnormal amplification of the CAG trinucleotide repeat in exon 10 of the ataxin-3 （ATXN3） gene, resulting in 70-81 CAG repeats in the patient, with a significant positive family history.展开更多
The neuronal microtubule-associated protein tau is abnormally hyperphosphorylated and aggregated into neurofibrillary tangles in the brains of individuals with Alzheimer＇s disease and related neurodegenerative disord...The neuronal microtubule-associated protein tau is abnormally hyperphosphorylated and aggregated into neurofibrillary tangles in the brains of individuals with Alzheimer＇s disease and related neurodegenerative disorders. The adult human brain expresses six isoforms of tau generated by alternative splicing of exons 2, 3, and 10 of its pre-mRNA. Exon 10 encodes the second microtubule-binding repeat of tau. Its alternative splicing produces tau isoforms with either three or four microtubule-binding repeats, termed 3R-tau and 4R- tau. In the normal adult human brain, the level of 3R-tau is approximately equal to that of 4R-tau. Several silent and intronic mutations of the tau gene associated with FTDP-17T （frontotemporal dementia with Parkinsonism linked to chromosome 17 and specifically characterized by tau pathology） only disrupt exon 10 splicing, but do not influence the primary sequence of the tau protein. Thus, abnormal exon 10 splicing is sufficient to cause neurodegeneration and dementia. Here, we review the regulation of tau exon 10 splicing by cis-elements and trans-factors and summarize all the mutations associated with FTDP-17T and related tauopathies. The findings suggest that correction of exon 10 splicing may be a potential target for tau exon 10 splicing-related tauopathies.展开更多
基金funded by Fengxian District Science Technology Commission Foundation of Shanghai,No.2010-101101,2011-110
文摘This study reports a case of a 75-year-old female Machado-Joseph disease patient exhibiting unstable walking and inaccurate hand holding for 8 months, which progressively worsened. Physical examination on admission showed cerebellar ataxia and a history of hypertension. Crania MRI demonstrated cerebellar and brain stem atrophy. Gene analysis showed abnormal amplification of the CAG trinucleotide repeat in exon 10 of the ataxin-3 （ATXN3） gene, resulting in 70-81 CAG repeats in the patient, with a significant positive family history.
基金supported by Nantong UniversityNew York State Institute for Basic Research in Developmental Disabilities+3 种基金by grants from the National Natural Science Foundation of China(81030059 and 81170317)the Basic Research Program of Education Department of Jiangsu Province,China(10KJA310040)the U.S.Alzheimer’s Association(Grant IIRG-10-173154)the Priority Academic Program Development of Jiangsu Higher Education Institutions(PAPD)of China
文摘The neuronal microtubule-associated protein tau is abnormally hyperphosphorylated and aggregated into neurofibrillary tangles in the brains of individuals with Alzheimer＇s disease and related neurodegenerative disorders. The adult human brain expresses six isoforms of tau generated by alternative splicing of exons 2, 3, and 10 of its pre-mRNA. Exon 10 encodes the second microtubule-binding repeat of tau. Its alternative splicing produces tau isoforms with either three or four microtubule-binding repeats, termed 3R-tau and 4R- tau. In the normal adult human brain, the level of 3R-tau is approximately equal to that of 4R-tau. Several silent and intronic mutations of the tau gene associated with FTDP-17T （frontotemporal dementia with Parkinsonism linked to chromosome 17 and specifically characterized by tau pathology） only disrupt exon 10 splicing, but do not influence the primary sequence of the tau protein. Thus, abnormal exon 10 splicing is sufficient to cause neurodegeneration and dementia. Here, we review the regulation of tau exon 10 splicing by cis-elements and trans-factors and summarize all the mutations associated with FTDP-17T and related tauopathies. The findings suggest that correction of exon 10 splicing may be a potential target for tau exon 10 splicing-related tauopathies.
