# C9orf72-ALS mutation drives basal mitophagy impairments in iNeurons

## TL;DR

This study shows that a common ALS mutation disrupts mitochondrial health in neurons by impairing autophagy, a key cellular cleanup process.

## Contribution

The study identifies a novel mechanism of autophagosome production impairment in C9orf72-ALS patient neurons, linking it to mitophagy deficits.

## Key findings

- C9orf72-ALS patient iNeurons have reduced mitochondrial membrane potential and basal mitophagy.
- Impaired autophagosome production and ULK1 recruitment to mitochondria contribute to mitophagy deficits.
- PINK1/Parkin and BNIP3 mitophagy pathways remain largely unaffected in these patient neurons.

## Abstract

ALS is a neurodegenerative disorder characterized by progressive upper and lower motor neuron loss. A GGGGCC hexanucleotide repeat expansion (HRE) in the C9orf72 gene is the most common mutation found in populations of European descent. Mitochondrial dysfunction has been observed in C9orf72-ALS patients and models of the disease, however, reports on mitochondrial clearance via mitophagy in C9orf72-ALS are limited.

iNeurons from C9orf72-ALS patients displayed reduced mitochondrial membrane potential and reduced basal mitophagy, due to reductions in autophagosome production and reduced ULK1 recruitment to mitochondria. No consistent changes to PINK1/Parkin or BNIP3 mitophagy pathways were observed.

Our data show that certain aspects of mitochondrial function is impaired in C9orf72-ALS patient iNeurons. An in-depth characterization of mitophagy suggests that a deficit in autophagosome production is responsible and provides further evidence that toxic gain-of-function mechanisms in C9orf72-ALS are responsible for autophagy deficits.