Recent advances in research on TDP-43 and FTLD-U

Tetsuaki Arai¹⁾, Masato Hasegawa²⁾, Takashi Nonaka²⁾, Fuyuki Kametani²⁾, Haruhiko Akiyama¹⁾

Department of Psychogeriatrics, Tokyo Institute of Psychiatry

Frontotemporal lobar degeneration（FTLD）is a common cause of dementia, second only to Alzheimer's disease in the population below 65 years of age. Two important work performed in 2006 significantly advanced a molecular understanding of FTLD. One was a discovery of mutations in progranulin（PGRN）gene in familial cases of FTLD with ubiquitin-positive, tau-negative inclusions（FTLD-U). Another was identification of TAR DNA-binding protein of 43 kDa（TDP-43）as a major component of ubiquitin-positive inclusions in FTLD-U and amyotrophic lateral sclerosis（ALS). Intraneuronal and/or glial accumulation of TDP-43 was further identified in inclusion body myopathy associated with Paget disease of bone and frontotemporal dementia caused by mutations in valosin-containing protein gene, familial FTLD-U linked to chromosome 9, and ALS/parkinsonism-dementia complex of Guam and Kii. These are now referred to as TDP-43 proteinopathy. Biochemical analyses of accumulated TDP-43 in affected brains consistently showed phosphorylation and fragmentation of TDP-43. Recent discovery of the missense mutations in the TDP-43 gene in families with dominantly inherited ALS proves a direct link between altered TDP-43 function and neurodegeneration. Elucidating the biochemical processes responsible for phosphorylation and fragmentation of TDP-43 and its neuronal toxicity may provide important insights into the pathogenesis of TDP-43 proteinopathy and other neurodegenerative disorders.

Address correspondence to Drs. Arai & Hasegawa, Department of Psychogeriatrics and Molecular Neurobiology, Tokyo Institute of Psychiatry (2-1-8 Kamikitazawa, Setagaya-ku, Tokyo 156-8585, Japan)