Rinsho Shinkeigaku (Clinical Neurology)

Symposium 2

Molecular pathogenesis of ALS in TDP43 era

Osamu Onodera, M.D., Ph.D.1)

1)Department of Molecular Neuroscience, Resource Branch for Brain Disease, Brain Research Institute, Niigata University

To clarify the molecular pathogenesis of amyotrophic lateral sclerosis (ALS) associated with TAR-DNA binding protein 43 kDd (TDP-43), the quality and quantity of TDP-43 take a crucial role. Regarding to the quality of TDP-43, TDP-43 has been reported as an aggregate-prone protein. Especially the C-terminus of the TDP-43 tends to form aggregate and has prion-like domain. Interestingly the mutations in the genes, which produce proteins with prion-like domain, have been identified in several neurodegenerative disorders. These results suggest the existence of the common property in the causative proteins for neurodegenerative disorders. For the quantity of TDP-43, the adequate amount of TDP-43 is necessary for maintaining cell function and cell survival. The amount of TDP-43 is tightly regulated by TDP-43. However the mechanism for autoregulation has not been fully elucidated. For the function of TDP-43, TDP-43 locates at stress granule, GEM and associates with the large genes and introns. Thus the alteration of TDP-43 may affect the function of stress granule, GEM and RNA metabolism in several genes. Moreover a U12 type spliceosome, which is matured in GEM, is decreased in ALS. The investigation of whether these dysfunctions explain the selective pathology in ALS provides a new therapeutic strategy for ALS.
Full Text of this Article in Japanese PDF (601K)

(CLINICA NEUROL, 53: 1077|1079, 2013)
key words: amyotrophic lateral sclerosis, TDP-43, prion, autoregulation, GEM

(Received: 30-May-13)