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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.
Highlights
Introduction Transactive response DNABinding Protein 43 (TDP-43, 43 kDa) has been characterized as a major component of cytoplasmic protein inclusion and surprisingly detectable in approximately 97% of patients with sporadic amyotrophic lateral sclerosis (ALS) and familial ALS or approximately 50–55% of frontotemporal dementia patients, indicating the possible link of Tar DNA-binding protein 43 (TDP-43) dysfunction to neurodegeneration[1]
We found that myosin IIB was localized to TDP-25 associated with abnormal mitochondria, whereas its inhibition failed to colocalize with TDP-25
To investigate the cellular pathogenic effect of TDP-43 C-terminal fragments (CTFs) (TDP-25) in cortical neurons, we examined its cellular localization in cultured cortical neurons
Summary
Introduction Transactive response DNABinding Protein 43 (TDP-43, 43 kDa) has been characterized as a major component of cytoplasmic protein inclusion and surprisingly detectable in approximately 97% of patients with sporadic ALS (sALS) and familial ALS (fALS) or approximately 50–55% of frontotemporal dementia patients, indicating the possible link of TDP-43 dysfunction to neurodegeneration[1]. We used FTD/ALS linked CTFs of TDP-43 (25 kDa) to investigate the role of myosin IIB in mitochondrial dysfunction and neurotoxicity associated with TDP-43 in cultured cortical neurons. Inhibition by myosin IIB siRNA reduced mitophagy and induced the accumulation of insoluble TDP-25 protein in the mitochondrial fraction, inducing neuronal cell death.
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