Rare and common genetic determinants of mitochondrial function determine severity but not risk of amyotrophic lateral sclerosis

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Harvey, C, Weinreich, M ORCID: 0009-0003-1576-3385, Lee, JAK ORCID: 0000-0001-9843-6475, Shaw, AC ORCID: 0000-0002-7321-7994, Ferraiuolo, L ORCID: 0000-0001-9118-5714, Mortiboys, H ORCID: 0000-0001-6439-0579, Zhang, S, Hop, PJ, Zwamborn, RAJ, van Eijk, K ORCID: 0000-0002-5612-4585 et al (show 15 more authors) , Julian, TH ORCID: 0000-0002-5488-5620, Moll, T ORCID: 0000-0001-5928-2514, Iacoangeli, A, Al Khleifat, A, Quinn, JP ORCID: 0000-0003-3551-7803, Pfaff, AL, Kõks, S, Poulton, J, Battle, SL, Arking, DE ORCID: 0000-0001-8980-8695, Snyder, MP, Veldink, JH, Kenna, KP, Shaw, PJ and Cooper-Knock, J ORCID: 0000-0002-0873-8689 (2024) Rare and common genetic determinants of mitochondrial function determine severity but not risk of amyotrophic lateral sclerosis Heliyon, 10 (3). e24975-. ISSN 2405-8440, 2405-8440

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Abstract

Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease involving selective vulnerability of energy-intensive motor neurons (MNs). It has been unclear whether mitochondrial function is an upstream driver or a downstream modifier of neurotoxicity. We separated upstream genetic determinants of mitochondrial function, including genetic variation within the mitochondrial genome or autosomes; from downstream changeable factors including mitochondrial DNA copy number (mtCN). Across three cohorts including 6,437 ALS patients, we discovered that a set of mitochondrial haplotypes, chosen because they are linked to measurements of mitochondrial function, are a determinant of ALS survival following disease onset, but do not modify ALS risk. One particular haplotype appeared to be neuroprotective and was significantly over-represented in two cohorts of long-surviving ALS patients. Causal inference for mitochondrial function was achievable using mitochondrial haplotypes, but not autosomal SNPs in traditional Mendelian randomization (MR). Furthermore, rare loss-of-function genetic variants within, and reduced MN expression of, ACADM and DNA2 lead to ∼50 % shorter ALS survival; both proteins are implicated in mitochondrial function. Both mtCN and cellular vulnerability are linked to DNA2 function in ALS patient-derived neurons. Finally, MtCN responds dynamically to the onset of ALS independently of mitochondrial haplotype, and is correlated with disease severity. We conclude that, based on the genetic measures we have employed, mitochondrial function is a therapeutic target for amelioration of disease severity but not prevention of ALS.

Item Type:	Article
Uncontrolled Keywords:	Project MinE ALS Sequencing Consortium
Divisions:	Faculty of Health & Life Sciences Faculty of Health & Life Sciences > Inst. Systems, Molec & Integrative Biology > Inst. Systems, Molec & Integrative Biology
Depositing User:	Symplectic Admin
Date Deposited:	19 Feb 2024 09:31
Last Modified:	28 Feb 2026 16:11
DOI:	10.1016/j.heliyon.2024.e24975
Related Websites:	Author Publisher
URI:	https://livrepository.liverpool.ac.uk/id/eprint/3178771
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