Rinsho Shinkeigaku (Clinical Neurology)

The TDP-43 proteinopathies, toward understanding of the molecular pathogenesis

Masato Hasegawa, M.D.1), Takashi Nonaka, M.D.1), Makiko Yamashita, M.D.1), Fuyuki Kametani, M.D.1), Tetsuaki Arai, M.D.2), Mari Yoshida, M.D.3), Yoshio Hashizume, M.D.3), Kuniaki Tsuchiya, M.D.4) and Haruhiko Akiyama, M.D.2)

1)Department of Molecular Neurobiology, Tokyo Institute of Psychiatry
2)Department of Psychogeriatrics, Tokyo Institute of Psychiatry
3)Department of Neuropathology, Institute for Medical Science of Aging, Aichi Medical University
4)Department of Laboratory Medicine and Pathology, Tokyo Metropolitan Matsuzawa Hospital

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)

(CLINICA NEUROL, 49: 783－785, 2009)
key words: FTLD, ALS, ubiquitin, phosphorylation, aggregation

(Received: 22-May-09)