臨床神経学

第50回日本神経学会総会(2009年)

<教育講演4>TDP-43蓄積症の概念と病態解明への展望

長谷川 成人1), 野中 隆1), 山下 万貴子1), 亀谷 富由樹1), 新井 哲明2), 吉田 眞理3), 橋詰 良夫3), 土谷 邦秋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〔〒156-8585 東京都世田谷区上北沢2-1-8〕
2)同 老年期精神疾患
3)愛知医大加齢研
4)都立松沢病院検査科

The TDP-43 proteinopathies: Toward understanding of the molecular pathogenesis. TAR DNA binding protein of 43 kDa (TDP-43), a heterogeneous nuclear ribonucleoprotein was identified as a major component of ubiquitin-positive inclusions in FTLD and ALS, and the concept of TDP-43 proteinopathies was proposed. Immunoblot and immunohistochemical analyses using multiple anti-phosphorylated TDP-43 antibodies revealed that hyperphosphorylated 18-26 kDa C-terminal fragments in addition to the full-length TDP-43 are major constituents of inclusions in FTLD-U and ALS. Recent discovery of mutations in the TDP-43 gene in familial and sporadic ALS, indicating that abnormality of TDP-43 protein cause neurodegeneration. It also strongly suggests that aggregation of TDP-43 or the process is responsible for neurodegeneration in FTLD-U and ALS. To investigate the molecular mechanisms of aggregation of TDP-43, we have established two cellular models for intracellular aggregates of TDP-43 similar to those in brains of TDP-43 proteinopathies patients. The first consists of SH-SY5Y cells expressing mutant TDP-43 that lacks both the nuclear localization signal (NLS) and residues 187-192 (ΔNLS & 187-192). The second model consists of SH-SY5Y cells expressing an aggregation-prone TDP-43 C-terminal fragment as a green fluorescent protein (GFP)-fusion. In these cells, round structures positive for both anti-pS409/410 and anti-Ub are observed. These results suggest that intracellular localization of TDP-43, truncation of TDP-43 and proteasomal dysfunction of cells may be involved in the pathological process of TDP-43 proteinopathies. We also found that two small compounds that have been reported to be beneficial in phase II clinical trials of Alzheimer's disease, inhibited the formation of TDP-43 aggregates in these two cellular models, suggesting that these compounds may be effective for the treatment of ALS and FTLD-U.
Full Text of this Article in Japanese PDF (415K)

(臨床神経, 49:783−785, 2009)
key words:FTLD, ALS, ユビキチン, リン酸化, 凝集

(受付日:2009年5月22日)