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C9orf72-ALS mutation drives basal mitophagy impairments in iNeurons
James A K Lee1, Chloe Moutin1, Sarah Granger1
1Division of Neuroscience, School of Medicine and Population and Health, Sheffield Institute for Translational Neuroscience, University of Sheffield, Sheffield, United Kingdom.
Frontiers in Cellular Neuroscience
|February 27, 2026
Summary
Motor neuron loss in ALS is linked to C9orf72 gene mutations. Patient-derived neurons show impaired mitochondrial function and reduced mitophagy due to fewer autophagosomes, suggesting toxic gain-of-function mechanisms.
Area of Science:
- Neuroscience
- Genetics
- Cell Biology
Background:
- Amyotrophic lateral sclerosis (ALS) involves motor neuron degeneration.
- C9orf72 gene hexanucleotide repeat expansion (HRE) is a common ALS mutation.
- Mitochondrial dysfunction is implicated in ALS, but mitophagy in C9orf72-ALS is understudied.
Purpose of the Study:
- Investigate mitochondrial function and mitophagy in C9orf72-ALS patient-derived neurons.
- Determine the mechanisms underlying mitophagy deficits in C9orf72-ALS.
Main Methods:
- Utilized induced neurons (iNeurons) from C9orf72-ALS patients.
- Assessed mitochondrial membrane potential and basal mitophagy levels.
- Examined key mitophagy pathways including ULK1, PINK1/Parkin, and BNIP3.
Main Results:
- C9orf72-ALS iNeurons exhibited reduced mitochondrial membrane potential.
- Basal mitophagy was decreased, primarily due to reduced autophagosome production.
- ULK1 recruitment to mitochondria was diminished, while PINK1/Parkin and BNIP3 pathways showed no consistent changes.
Conclusions:
- Mitochondrial function is impaired in C9orf72-ALS patient iNeurons.
- Deficits in autophagosome production underlie the observed mitophagy impairment.
- Findings support toxic gain-of-function mechanisms in C9orf72-ALS contributing to autophagy deficits.
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