Rinsho Shinkeigaku (Clinical Neurology)

The 49th Annual Meeting of the Japanese Society of Neurology

Frontotemporal dementia (FTD) and genetic mutations including progranulin gene

Tetsuaki Arai, M.D.1), Masato Hasegawa, Ph.D.2), Masugi Nishihara, Ph.D.3), Takashi Nonaka, Ph.D.2), Fuyuki Kametani, Ph.D.2), Mari Yoshida, M.D.4), Yoshio Hashizume, M.D.4), Thomas G Beach, M.D.5), Mitsuya Morita, M.D.6), Imaharu Nakano, M.D.6), Tatsuro Oda, M.D.7), Kuniaki Tsuchiya, M.D.8) and Haruhiko Akiyama, M.D.1)

1)Department of Psychogeriatrics, Tokyo Institute of Psychiatry, Tokyo Metropolitan Organization for Medical Research
2)Department of Molecular Neurobiology, Tokyo Institute of Psychiatry, Tokyo Metropolitan Organization for Medical Research
3)Department of Veterinary Physiology, Veterinary Medical Science, The University of Tokyo
4)Department of Neuropathology, Institute for Medical Science of Aging, Aichi Medical University
5)Sun Health Research Institute
6)Department of Neurology, Jichi Medical University
7)Department of Neuropsychiatry, National Shimofusa Mental Hospital
8)Department of Laboratory Medicine and Pathology, Tokyo Metropolitan Matsuzawa Hospital

Research on familial frontotemporal lobar degeneration (FTLD) has led to the discovery of disease-causing genes: microtubule-associated protein tau (MAPT), progranulin (PGRN) and valosin-containing protein (VCP). TAR DNA-binding protein of 43 kDa (TDP-43) has been identified as a major component of tau-negative ubiquitin-positive inclusions in familial and sporadic FTLD and amyotrophic lateral sclerosis (ALS), which are now referred to as TDP-43 proteinopathy. Recent findings of mutations in TDP-43 gene in familial and sporadic ALS cases confirm the pathogenetic role for TDP-43 in neurodegeneration.
TDP-43 proteinopathies have been classified into 4 pathological subtypes. Type 1 is characterized by numerous dystrophic neurites (DNs), Type 2 has numerous neuronal cytoplasmic inclusions (NCIs), Type 3 has NCIs and DNs and Type 4 has neuronal intranuclear inclusions (NIIs) and DNs. There is a close relationship between such pathological subtypes of TDP-43 proteinopathy and the immunoblot pattern of C-terminal fragments of accumulated TDP-43. These results parallel our earlier findings of differing C-terminal tau fragments in progressive supranuclear palsy and corticobasal degeneration, despite identical composition of tau isoforms. Taken together, these results suggest that elucidating the mechanism of C-terminal fragment origination may shed light on the pathogenesis of several neurodegenerative disorders involving TDP-43 proteinopathy and tauopathy.
Full Text of this Article in Japanese PDF (325K)

(CLINICA NEUROL, 48: 990|993, 2008)
key words: inclusions, phosphorylation, fragment, neurodegeneration, dementia

(Received: 17-May-08)