Parkin is a disease modifier in the mutant SOD1 mouse model of ALS

Abstract Mutant Cu/Zn superoxide dismutase ( SOD1) causes mitochondrial alterations that contribute to motor neurondemise in amyotrophic lateral sclerosis(ALS). When mitochondria are damaged, cells activate mitochondria quality control (MQC) mechanisms leading to mitophagy. Here, we show that in the spinal cord of G93A mutant SOD1transgenic mice ( SOD1‐G93A mice), the autophagy receptor p62 is recruited to mitochondria and mitophagyis activated. Furthermore, the mitochondrial ubiquitin ligase Parkinand mitochondrial dynamics proteins, such as Miro1, and Mfn2, which are ubiquitinated by Parkin, and the mitochondrial biogenesisregulator PGC1α are depleted. Unexpectedly, Parkingenetic ablation delays disease progression and prolongs survival in SOD1‐G93A mice, as it slows down motor neuronloss and muscle denervation and attenuates the depletion of mitochondrial dynamics proteins and PGC1α. Our results indicate that Parkinis a disease modifier in ALS, because chronic Parkin‐mediated MQC activation depletes mitochondrial dynamics‐related proteins, inhibits mitochondrial biogenesis, and worsens mitochondrial dysfunction.