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Published (Version of Record)CC BY V4.0, Open Access
Journal article
Rare and common genetic determinants of mitochondrial function determine severity but not risk of amyotrophic lateral sclerosis
Heliyon, Vol.10(3), e24975
2024
PMCID: PMC10839612
PMID: 38317984
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.
Details
- Title
- Rare and common genetic determinants of mitochondrial function determine severity but not risk of amyotrophic lateral sclerosis
- Authors/Creators
- Calum HarveyMarcel WeinreichJames A.K. LeeAllan C. ShawLaura FerraiuoloHeather MortiboysSai ZhangPaul J. HopRamona A.J. ZwambornKristel van EijkThomas H. JulianTobias MollAlfredo IacoangeliAhmad Al KhleifatJohn P. QuinnAbigail L. PfaffSulev KõksJoanna PoultonStephanie L. BattleDan E. ArkingMichael P. SnyderJan H. VeldinkKevin P. KennaPamela J. ShawJohnathan Cooper-Knock
- Publication Details
- Heliyon, Vol.10(3), e24975
- Publisher
- Elsevier Ltd.
- Identifiers
- 991005634465407891
- Copyright
- © 2024 The Authors.
- Murdoch Affiliation
- Centre for Molecular Medicine and Innovative Therapeutics
- Language
- English
- Resource Type
- Journal article
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- Collaboration types
- Domestic collaboration
- International collaboration
- Citation topics
- 1 Clinical & Life Sciences
- 1.52 Neurodegenerative Diseases
- 1.52.765 ALS Mechanisms
- Web Of Science research areas
- Clinical Neurology
- ESI research areas
- Neuroscience & Behavior