Neuropathy due to impaired axonal transport of non-fragmented mitochondria in MYH14 mutation carriers

Finsterer, Josef

doi:10.1016/j.ebiom.2019.09.056

Cited by 1 publication

(1 citation statement)

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“…Disrupting myosin IIB activity in cultured neurons alters the dendritic spine development 15,16 . Recently, a genetic mutation in Myh14 (Myosin IIC) was associated with impaired axonal transport of nonfragmented mitochondria, thereby implicating it in neurodegeneration 17 . However, the role of myosin II in neurodegeneration associated with TDP-43 and its link to mitochondrial dysfunction remains unknown.…”

Section: Introductionmentioning

confidence: 99%

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

et al. 2020

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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.

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Section: Introductionmentioning

confidence: 99%