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

• Main Authors: Gloria M Palomo, Veronica Granatiero, Hibiki Kawamata, Csaba Konrad, Michelle Kim, Andrea J Arreguin, Dazhi Zhao, Teresa A Milner, Giovanni Manfredi
• Format: Article
• Language: English
• Published: Wiley 2018-10-01
• Series: EMBO Molecular Medicine
• Subjects: amyotrophic lateral sclerosis; mitochondria quality control; mitophagy; Parkin; SOD1
• Online Access: https://doi.org/10.15252/emmm.201808888
• ISSN: 1757-4676; 1757-4684

Abstract Mutant Cu/Zn superoxide dismutase (SOD1) causes mitochondrial alterations that contribute to motor neuron demise 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 SOD1 transgenic mice (SOD1‐G93A mice), the autophagy receptor p62 is recruited to mitochondria and mitophagy is activated. Furthermore, the mitochondrial ubiquitin ligase Parkin and mitochondrial dynamics proteins, such as Miro1, and Mfn2, which are ubiquitinated by Parkin, and the mitochondrial biogenesis regulator PGC1α are depleted. Unexpectedly, Parkin genetic ablation delays disease progression and prolongs survival in SOD1‐G93A mice, as it slows down motor neuron loss and muscle denervation and attenuates the depletion of mitochondrial dynamics proteins and PGC1α. Our results indicate that Parkin is a disease modifier in ALS, because chronic Parkin‐mediated MQC activation depletes mitochondrial dynamics‐related proteins, inhibits mitochondrial biogenesis, and worsens mitochondrial dysfunction.