Cells (Dec 2022)

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

  • Saebom Lee,
  • Hye Guk Ryu,
  • Sin Ho Kweon,
  • Hyerynn Kim,
  • Hyeonwoo Park,
  • Kyung-Ha Lee,
  • Sang-Min Jang,
  • Chan Hyun Na,
  • Sangjune Kim,
  • Han Seok Ko

DOI
https://doi.org/10.3390/cells11243972
Journal volume & issue
Vol. 11, no. 24
p. 3972

Abstract

Read online

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.

Keywords