Rinsho Shinkeigaku (Clinical Neurology)


Recent progress in ALS research: ALS and TDP-43

Shigeki Kuzuhara, M.D., Ph.D.

Department of Neurology, National Center Hospital of Neurology and Psychiatry

Selective involvements of upper and lower motor neurons have been regarded as one of the most characteristic features of amyotrophic lateral sclerosis (ALS). However, evidences of more extensive involvements affecting the systems other than the pure motor systems have been accumulated since the discovery of ubiquitin-positive inclusions (UbIs) in ALS, ALS-dementia (ALS-D), and frontotemporal lobar degeneration (FTLD) with UbIs (FTLD-U). A breakthrough occurred in ALS research in October 2006, when TAR DNA-binding protein-43 (TDP-43) was identified as the core protein that is ubiquitinated in the cytoplasm, neurites and nucleus as UbIs. Antibody to phosphorylated TDP-43 selectively reacts to the inclusions and Western blotting demonstrates abnormal bands of phosphorylated TDP-43 in the brains of patients with ALS/FTLD-U. Similar findings were observed in ALS/parkinsonism-dementia complex (PDC) of Guam and Kii peninsula. These diseases are lumped in the "TDP-43 proteinopathy". In early 2008, several mutations of the TDP-43 gene were identified as the causative gene of autosomal-dominant familial ALS without SOD1 gene mutations. These findings suggest that abnormalities of TDP-43 directly or indirectly produce severe motor neuron degeneration. TDP-43 is thus one of the key proteins causing TDP-43 proteinopathies such as ALS, ALS-D, FTLD-U, and ALS/PDC of Guam and Kii. New revolutionary developments on ALS research for molecular mechanism and therapy are expected.
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(CLINICA NEUROL, 48: 625|633, 2008)
key words: ALS, TDP-43, frontotemporal lobar degeneration, ubiquitin, familial ALS

(Received: 18-Aug-08)