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000287630 1001_ $$aHarvey, Calum$$b0
000287630 245__ $$aRare and common genetic determinants of mitochondrial function determine severity but not risk of amyotrophic lateral sclerosis.
000287630 260__ $$aLondon [u.a.]$$bElsevier$$c2024
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000287630 520__ $$aAmyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease involving selective vulnerability of energy-intensive motor neurons (MNs). It has been unclear whether mitochondrial function is an upstream driver or a downstream modifier of neurotoxicity. We separated upstream genetic determinants of mitochondrial function, including genetic variation within the mitochondrial genome or autosomes; from downstream changeable factors including mitochondrial DNA copy number (mtCN). Across three cohorts including 6,437 ALS patients, we discovered that a set of mitochondrial haplotypes, chosen because they are linked to measurements of mitochondrial function, are a determinant of ALS survival following disease onset, but do not modify ALS risk. One particular haplotype appeared to be neuroprotective and was significantly over-represented in two cohorts of long-surviving ALS patients. Causal inference for mitochondrial function was achievable using mitochondrial haplotypes, but not autosomal SNPs in traditional Mendelian randomization (MR). Furthermore, rare loss-of-function genetic variants within, and reduced MN expression of, ACADM and DNA2 lead to ∼50 % shorter ALS survival; both proteins are implicated in mitochondrial function. Both mtCN and cellular vulnerability are linked to DNA2 function in ALS patient-derived neurons. Finally, MtCN responds dynamically to the onset of ALS independently of mitochondrial haplotype, and is correlated with disease severity. We conclude that, based on the genetic measures we have employed, mitochondrial function is a therapeutic target for amelioration of disease severity but not prevention of ALS.
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000287630 7001_ $$0P:(DE-He78)74b9c8e36d19d91fcd9485c70a038d13$$aWeinreich, Marcel$$b1$$udkfz
000287630 7001_ $$aLee, James A K$$b2
000287630 7001_ $$aShaw, Allan C$$b3
000287630 7001_ $$aFerraiuolo, Laura$$b4
000287630 7001_ $$aMortiboys, Heather$$b5
000287630 7001_ $$aZhang, Sai$$b6
000287630 7001_ $$aHop, Paul J$$b7
000287630 7001_ $$aZwamborn, Ramona A J$$b8
000287630 7001_ $$avan Eijk, Kristel$$b9
000287630 7001_ $$aJulian, Thomas H$$b10
000287630 7001_ $$aMoll, Tobias$$b11
000287630 7001_ $$aIacoangeli, Alfredo$$b12
000287630 7001_ $$aAl Khleifat, Ahmad$$b13
000287630 7001_ $$aQuinn, John P$$b14
000287630 7001_ $$aPfaff, Abigail L$$b15
000287630 7001_ $$aKõks, Sulev$$b16
000287630 7001_ $$aPoulton, Joanna$$b17
000287630 7001_ $$aBattle, Stephanie L$$b18
000287630 7001_ $$aArking, Dan E$$b19
000287630 7001_ $$aSnyder, Michael P$$b20
000287630 7001_ $$aConsortium, Project MinE ALS Sequencing$$b21$$eCollaboration Author
000287630 7001_ $$aVeldink, Jan H$$b22
000287630 7001_ $$aKenna, Kevin P$$b23
000287630 7001_ $$aShaw, Pamela J$$b24
000287630 7001_ $$aCooper-Knock, Johnathan$$b25
000287630 773__ $$0PERI:(DE-600)2835763-2$$a10.1016/j.heliyon.2024.e24975$$gVol. 10, no. 3, p. e24975 -$$n3$$pe24975$$tHeliyon$$v10$$x2405-8440$$y2024
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