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EMBO Mol Med. 2018 Oct;10(10). pii: e8888. doi: 10.15252/emmm.201808888.

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

Author information

1
Feil Family Brain and Mind Research Institute, Weill Cornell Medicine, New York, NY, USA.
2
Harold and Margaret Milliken Hatch Laboratory of Neuroendocrinology, The Rockefeller University, New York, NY, USA.
3
Feil Family Brain and Mind Research Institute, Weill Cornell Medicine, New York, NY, USA gim2004@med.cornell.edu.

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.

KEYWORDS:

Parkin; SOD1; amyotrophic lateral sclerosis; mitochondria quality control; mitophagy

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