c-Abl Regulates the Pathological Deposition of TDP-43 via Tyrosine 43 Phosphorylation

Author:

Lee Saebom,Ryu Hye GukORCID,Kweon Sin Ho,Kim Hyerynn,Park Hyeonwoo,Lee Kyung-Ha,Jang Sang-Min,Na Chan Hyun,Kim SangjuneORCID,Ko Han SeokORCID

Abstract

Non-receptor tyrosine kinase, c-Abl plays a role in the pathogenesis of several neurodegenerative disorders such as Alzheimer’s disease and Parkinson’s disease. Here, we found that TDP-43, which was one of the main proteins comprising pathological deposits in amyotrophic lateral sclerosis (ALS), is a novel substrate for c-Abl. The phosphorylation of tyrosine 43 of TDP-43 by c-Abl led to increased TDP-43 levels in the cytoplasm and increased the formation of G3BP1-positive stress granules in SH-SY5Y cells. The kinase-dead mutant of c-Abl had no effect on the cytoplasmic localization of TDP-43. The expression of phosphor-mimetic mutant Y43E of TDP-43 in primary cortical neurons accumulated the neurite granule. Furthermore, the phosphorylation of TDP-43 at tyrosine 43 by c-Abl promoted the aggregation of TDP-43 and increased neuronal cell death in primary cortical neurons, but not in c-Abl–deficient primary cortical neurons. Identification of c-Abl as the kinase of TDP43 provides new insight into the pathogenesis of ALS.

Funder

National Institutes of Health

National Research Foundation of Korea (NRF) funded by the Korean government

Publisher

MDPI AG

Subject

General Medicine

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