% IMPORTANT: The following is UTF-8 encoded.  This means that in the presence
% of non-ASCII characters, it will not work with BibTeX 0.99 or older.
% Instead, you should use an up-to-date BibTeX implementation like “bibtex8” or
% “biber”.

@ARTICLE{Harvey:287630,
      author       = {C. Harvey and M. Weinreich$^*$ and J. A. K. Lee and A. C.
                      Shaw and L. Ferraiuolo and H. Mortiboys and S. Zhang and P.
                      J. Hop and R. A. J. Zwamborn and K. van Eijk and T. H.
                      Julian and T. Moll and A. Iacoangeli and A. Al Khleifat and
                      J. P. Quinn and A. L. Pfaff and S. Kõks and J. Poulton and
                      S. L. Battle and D. E. Arking and M. P. Snyder and J. H.
                      Veldink and K. P. Kenna and P. J. Shaw and J. Cooper-Knock},
      collaboration = {P. M. A. S. Consortium},
      title        = {{R}are and common genetic determinants of mitochondrial
                      function determine severity but not risk of amyotrophic
                      lateral sclerosis.},
      journal      = {Heliyon},
      volume       = {10},
      number       = {3},
      issn         = {2405-8440},
      address      = {London [u.a.]},
      publisher    = {Elsevier},
      reportid     = {DKFZ-2024-00284},
      pages        = {e24975},
      year         = {2024},
      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.},
      cin          = {A230},
      ddc          = {000},
      cid          = {I:(DE-He78)A230-20160331},
      pnm          = {311 - Zellbiologie und Tumorbiologie (POF4-311)},
      pid          = {G:(DE-HGF)POF4-311},
      typ          = {PUB:(DE-HGF)16},
      pubmed       = {pmid:38317984},
      pmc          = {pmc:PMC10839612},
      doi          = {10.1016/j.heliyon.2024.e24975},
      url          = {https://inrepo02.dkfz.de/record/287630},
}