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@ARTICLE{OBrien:302327,
      author       = {D. O'Brien and E. Alhathli and C. Harwood and D.
                      Bhattacharya and K. Gupta and T. Julian and M. Weinreich$^*$
                      and R. J. H. West and D. Wang and R. P. Byrne and R. L.
                      McLaughlin and J. Wuu and M. Benatar and J. Cooper-Knock and
                      P. J. Shaw},
      title        = {{E}xtreme exercise in males is linked to m{TOR} signalling
                      and onset of amyotrophic lateral sclerosis.},
      journal      = {Brain},
      volume       = {nn},
      issn         = {0006-8950},
      address      = {Oxford},
      publisher    = {Oxford Univ. Press},
      reportid     = {DKFZ-2025-01322},
      pages        = {nn},
      year         = {2025},
      note         = {epub},
      abstract     = {Amyotrophic lateral sclerosis (ALS) is thought to be caused
                      by interaction between genetic and environmental factors
                      leading to motor neuron (MN) degeneration. Physical exercise
                      has been linked to ALS but controversy remains. A key
                      question is to determine which individuals might be at risk
                      of exercise-associated ALS, because unnecessary avoidance of
                      exercise could be harmful. We implemented complementary
                      strategies including Mendelian randomization and multiple
                      questionnaire-based measures of physical exercise in
                      different cohorts. We include a prospective study in UK
                      Biobank participants where we could test for a relationship
                      between exercise and the timing of future ALS symptom onset.
                      To interrogate the molecular basis of our observations we
                      performed a genetic association study of 'extreme' exercise,
                      equivalent to >6 hours of strenuous exercise or >12 hours of
                      any leisure-time exercise per week. Our data suggest that
                      the link between increased physical exercise and ALS is
                      particularly important for males who perform the most
                      activity; with no evidence of a link in females. We
                      determined that extreme exercise in males is associated with
                      loss-of-function genetic variants within a number of
                      mammalian target of rapamycin (mTOR) signalling genes that
                      are also differentially expressed in ALS spinal cord.
                      Activity-induced mTOR signalling has been shown to
                      selectively benefit MN. Therefore, our findings could imply
                      that moderate exercise is neuroprotective via enhanced mTOR
                      signalling, but extreme exercise in men is associated with
                      neurotoxicity and ALS via a failure of this mechanism. There
                      was no significant overlap between genes associated with
                      extreme exercise and those associated with ALS risk,
                      consistent with a true gene-environment interaction rather
                      than a shared genetic basis. We are not yet able to make
                      individual-level recommendations regarding exercise and risk
                      of ALS, but our conclusions should focus future
                      investigation.},
      keywords     = {Exercise (Other) / amyotrophic lateral sclerosis (ALS)
                      (Other) / gene-environment interaction (Other) / mammalian
                      target of rapamycin (mTOR) signalling (Other)},
      cin          = {A230},
      ddc          = {610},
      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:40577240},
      doi          = {10.1093/brain/awaf235},
      url          = {https://inrepo02.dkfz.de/record/302327},
}