第51回日本神経学会総会
＜シンポジウム13―1＞筋萎縮性側索硬化症の病因TDP-43およびFUS/TLS研究の最前線
ALS，FTLD の病因TDP-43の分子解剖
長谷川 成人1）, 新井 哲明2）3）, 野中 隆1）, 辻 浩史1）4）, 山下 万貴子1）, 細川 雅人2）, 亀谷 富由樹1）, 玉岡 晃4）, 秋山 治彦2）
1）東京都精神医学総合研究所分子神経生物学研究チーム〔〒156―8585 東京都世田谷区上北沢2―1―8〕
2）同 老年期精神疾患研究チーム
3）筑波大学大学院人間総合科学研究科精神病態医学分野
4）同 人間総合科学研究科神経病態医学分野
Proteomic and immunochemical analyses have shown that hyperphosphorylated TDP-43 is a major component of ubiquitin-positive inclusions from brain of frontotemporal lobar degeneration (FTLD) patients. In 2008, TDP-43 gene mutations were discovered in familial and sporadic amyotrophic lateral sclerosis (ALS), indicating that TDP-43 protein abnormality is associated with neurodegeneration. We raised antibodies against 36 synthetic phosphopeptides and demonstrated that abnormal phosphorylation takes place in the C-terminal region of TDP-43. One antibody, pS409/410, stained the inclusions in both FTLD and ALS brains, with no nuclear staining. Immunoblotting revealed the presence of hyperphosphorylated 45 kDa band, smearing substances and 18-26 kDa fragments in deposits, and the band patterns were different between FTLD and ALS. Overexpression of TDP-43 C-terminal fragments as GFP-fusions resulted in formation of inclusions positive for antibodies to phosphorylated TDP-43 and ubiquitin. We further investigated the protease-resistant TDP-43 and found that it is also different between ALS and FTLD, supporting the idea that the different band patterns reflect different conformations of abnormal TDP-43. Interestingly, the C-terminal band pattern is indistinguishable among brain regions and spinal cord in each individual patient. These results suggest that abnormal TDP-43 produced in a cell may be transferred to different regions and propagated during disease progression.
Full Text of this Article in Japanese PDF (196K)
(臨床神経, 50：937−939, 2010)
key words：アミロイド，プリオン，リン酸化，ユビキチン化，伝播
（受付日：2010年5月22日）
