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

Gloria M Palomo,Andrea J Arreguin,Veronica Granatiero,Teresa A Milner,Dazhi Zhao,Giovanni Manfredi,Michelle Kim,Csaba Konrad,Hibiki Kawamata

doi:10.15252/emmm.201808888

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.

Highlights

Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease caused by the demise of upper and lower motor neurons
We investigated whether mitochondrial damage induces MCQ activity in the spinal cord of SOD1-G93A mice in the B6SJL genetic background, which has an average lifespan of 129 days (Gurney et al, 1994)
Because it was shown that SOD1 aggregates are formed both in cytosol and in mitochondria of G93A-SOD1 mouse spinal cord (Vijayvergiya et al, 2005), we looked at the mitochondrial fractions separately to assess whether they were affected by Parkin knockout

Summary

Introduction

Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease caused by the demise of upper and lower motor neurons. Of the numerous forms of inherited ALS (Bettencourt & Houlden, 2015), approximately 20% are caused by mutations in the gene Cu/Zn superoxide dismutase (SOD1), which was the first ALS gene discovered (Rosen et al, 1993). Over 180 different mutations in SOD1 have been identified and associated with the disease (Wroe et al, 2008). After the discovery of SOD1, many other genes have been associated with ALS (Ghasemi & Brown, 2017). These genes encode for proteins involved in different cellular pathways, from RNA metabolism, to nuclear transport, to protein and organellar quality control, highlighting the complexity of ALS pathogenesis (Peters et al, 2015). Numerous evidence of mitochondrial functional and morphological alterations indicates that these organelles are predominantly involved in ALS pathogenesis (Smith et al, 2017)

Methods

Results

Conclusion