Abstract
Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease characterized by the progressive demise of motor neurons. One of the causes of familial ALS is the mutation of the gene encoding superoxide dismutase 1 (SOD1), which leads to abnormal protein aggregates. How SOD1 aggregation drives ALS is still poorly understood. Recently, ALS pathogenesis has been functionally implicated in mitophagy, specifically the clearance of damaged mitochondria. Here, to understand this mechanism, we investigated the relationship between the mitophagy receptor optineurin and SOD1 aggregates. We found that mutant SOD1 (mSOD1) proteins associate with and then sequester optineurin, which is required to form the mitophagosomes, to aggregates in N2a cells. Optineurin recruitment into mSOD1 aggregates resulted in a reduced mitophagy flux. Furthermore, we observed that an exogenous augmentation of optineurin alleviated the cellular cytotoxicity induced by mSOD1. Taken together, these studies demonstrate that ALS-linked mutations in SOD1 interfere with the mitophagy process through optineurin sequestration, suggesting that the accumulation of damaged mitochondria may play a crucial role in the pathophysiological mechanisms contributing to ALS.
Highlights
Amyotrophic lateral sclerosis (ALS) is a late-onset neurodegenerative disease characterized by the progressive death of both lower and upper motor neurons in the brain and spinal cord [1,2]
It was demonstrated that mutations in the gene encoding OPTN were found in neuronal cells of some familial and sporadic ALS patients, in which OPTN proteins formed protein inclusions, as shown in ALS-linked mutant proteins such as superoxide dismutase 1 (SOD1) and TDP-43 [30]
These results indicate that OPTN interacts with the ALS-linked mutant SOD1 proteins, A4V and G93A
Summary
Amyotrophic lateral sclerosis (ALS) is a late-onset neurodegenerative disease characterized by the progressive death of both lower and upper motor neurons in the brain and spinal cord [1,2]. Continuous deterioration of the muscular-related nervous system causes defective swallowing, speaking, and breathing and muscle weakness in ALS. Except in the case of mild progression, ALS typically leads to death within 3–5 years after disease onset [3,4]. Most cases of ALS occur without a detectable hereditary factor, but mutations in numerous genes have been linked to several cases of familial ALS (fALS) [8]. 90% of cases are sporadic (sALS), but 10% of ALS cases are familial. Mutations in more than 20 different genes have been identified as contributing to ALS [9]
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
