A cellular model for intracellular TDP-43 aggregates

Takashi Nonaka¹⁾, Tetsuaki Arai²⁾, Haruhiko Akiyama²⁾, Masato Hasegawa¹⁾

¹⁾Department of Molecular Neurobiology, Tokyo Institute of Psychiatry
²⁾Department of Psychogeriatrics, Tokyo Institute of Psychiatry

TAR DNA binding protein of 43 kDa (TDP-43) was identified as a major component of the ubiquitin-positive inclusions found in frontotemporal lobar degeneration (FTLD) and amyotrophic lateral sclerosis (ALS). Here, we report that aggregation of TDP-43 similar to those found in brains of FTLD and ALS is recapitulated in SH-SY5Y. Deletion of the sequences near the nuclear localization signal resulted in cytoplasmic localization of TDP-43, whereas the deletion mutant lacking the region around RNA recognition motif localized in nuclei, forming unique dot-like structures. Proteasome inhibition caused these to assemble into round aggregates reactive with anti-phosphorylated TDP-43 and anti-ubiquitin antibodies. A green fluorescent protein-tagged N-Terminal or C-terminal fragments of TDP-43 also promoted formation of the abnormal intracellular inclusions. These unique cellular models of TDP-43 proteinopathies provide a molecular basis for the formation of ubiquitin-positive inclusions.

Address correspondence to Dr. Takashi Nonaka, Department of Molecular Neurobiology, Tokyo Institute of Psychiatry (2-1-8 Kamikitazawa, Setagaya-ku, Tokyo 156-8585, Japan)