2011 Fiscal Year Final Research Report
Identification for serum biomarker for ALS associated with the function of TDP-43
| Project/Area Number |
22659169
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| Research Category |
Grant-in-Aid for Challenging Exploratory Research
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| Allocation Type | Single-year Grants |
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| Research Field |
Neurology
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| Research Institution | Niigata University |
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Principal Investigator |
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| Project Period (FY) |
2010 – 2011
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| Keywords | 神経分子病態学 |
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| Research Abstract |
Amyotrophic lateral sclerosis(ALS) is an adult-onset neurodegenerative disease caused by selective loss of motor neurons. In the ALS motor neurons, TAR DNA-binding protein of 43 kDa(TDP-43) is dislocated from the nucleus to cytoplasm and forms inclusions, suggesting that loss of a nuclear function of TDP-43 may underlie the pathogenesis of ALS. TDP-43 functions in RNA metabolism include regulation of transcription, mRNA stability, and alternative splicing of pre-mRNA. However, a function of TDP-43 in tissue affected with ALS has not been elucidated. We sought to identify the molecular indicators reflecting on a TDP-43 function. Using exon array analysis, we observed a remarkable alteration of splicing in several genes as a result of the depletion of TDP-43 expression in two types of cultured cells. In the cells treated with TDP-43 siRNA, wild-type splicing variants decreased and transcripts lacking some exons increased. The RNA binding ability of TDP-43 was necessary for inclusion and exclusion of these exons. Moreover, we found an increment of splicing varinats in motor cortex, spinal cord and spinal motor neurons collected by laser microdissection with ALS. Our results suggest a loss of TDP-43 function in tissues affected with ALS, supporting the hypothesis that a loss of function of TDP-43 underlies the pathogenesis of ALS.
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Research Products
(9 results)
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[Journal Article] Pri mary lateral sclerosis : Upper-motor-pred ominant amyotrophic lateral sclerosis with frontotemporal lobar degeneration-immunohistochemical and biochemical analyses of TDP-432011
Author(s)
Kosaka T, Fu YJ, Shiga A, Ishidaira H, Tan CF, Tani T, Koike R, Onodera O, Ni shizawa M, Kakita A, Takahashi H
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Journal Title
DOI
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[Presentation] Aberrant splicing of POLDIP3 gene in motor neuron with ALS2011
Author(s)
A. SHIGA, T. ISHIHARA, A. MIYASHITA, T. KATO, M. KUWABARA, A. YOKOSEKI, R. KUWANO, A. KAKITA, H. TAKAHASHI, M. NISHIZAWA, O. ONODERA
Organizer
米国神経科学会
Year and Date
20110000
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