Nonmuscle myosin IIB regulates Parkin-mediated mitophagy associated with amyotrophic lateral sclerosis-linked TDP-43

Mi Hee Jun, Jae Woo Jang, Pureum Jeon, Soo Kyung Lee, Sang Hoon Lee, Ha Eun Choi, You Kyung Lee, Haneul Choi, Sang Won Park, Jeongyeon Kim, Deok Jin Jang, Jin A. Lee

Research output: Contribution to journalArticlepeer-review

9 Scopus citations

Abstract

C-terminal fragments of Tar DNA-binding protein 43 (TDP-43) have been identified as the major pathological protein in several neurodegenerative diseases, including amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). However, how they affect cellular toxicity and neurodegeneration, including the modulation process remains unknown. This study revealed that the C-terminal fragment of TDP-43 (TDP-25) was localized primarily to mitochondria and caused abnormal mitochondrial morphology, inducing Parkin-mediated mitophagy. Also, we discovered that the knockdown of selective autophagy receptors, such as TAX1BP, Optineurin, or NDP52 caused TDP-25 accumulation, indicating that TDP-25 was degraded by mitophagy. Interestingly, myosin IIB, a nonmuscle type of myosin and actin-based motor protein, is mostly colocalized to TDP-25 associated with abnormal mitochondria. In addition, myosin IIB inhibition by siRNA or blebbistatin induced mitochondrial accumulation of insoluble TDP-25 and Tom20, and reduced neuronal cell viability. Our results suggest a novel role of myosin IIB in mitochondrial degradation of toxic TDP-25. Therefore, we proposed that regulating myosin IIB activity might be a potential therapeutic target for neurodegenerative diseases associated with TDP-43 pathology.

Original languageEnglish
Article number952
JournalCell Death and Disease
Volume11
Issue number11
DOIs
StatePublished - 1 Nov 2020

Fingerprint

Dive into the research topics of 'Nonmuscle myosin IIB regulates Parkin-mediated mitophagy associated with amyotrophic lateral sclerosis-linked TDP-43'. Together they form a unique fingerprint.

Cite this