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@MISC{Rezaei:277510,
      author       = {Rezaei, Ali and Edbauer, Dieter and Günes, Zeynep Irem and
                      Liebscher, Sabine and Bauernschmitt, F. and Beltran, E.},
      title        = {{D}ataset: {C}orrection of dysregulated lipid metabolism
                      normalizes gene expression in oligodendrocytes and prolongs
                      lifespan in female poly-{GA} {C}9orf72 mouse model},
      publisher    = {Gene Expression Omnibus},
      reportid     = {DZNE-2025-00421},
      year         = {2025},
      abstract     = {Summary: These sequences support the following paper
                      abstract: "Clinical and genetic research links altered
                      cholesterol metabolism with ALS development and progression,
                      yet pinpointing specific pathomechanisms remain challenging.
                      We investigated how cholesterol dysmetabolism interacts with
                      protein aggregation, demyelination, and neuronal loss in
                      ALS. Bulk RNAseq transcriptomics showed decreased
                      cholesterol biosynthesis and increased cholesterol export in
                      ALS mouse models (GA-Nes, GA-CFP, rNLS8) and patient samples
                      (spinal cord), suggesting an adaptive response to
                      cholesterol overload. Consequently, we assessed the efficacy
                      of the cholesterol-binding drug
                      2-hydroxypropyl-β-cyclodextrin (CD) in a fast-progressing
                      C9orf72 ALS mouse model with extensive poly-GA expression
                      and myelination deficits. CD treatment normalized
                      cholesteryl ester levels, lowered neurofilament light chain
                      levels, and prolonged lifespan in female but not male GA-Nes
                      mice, without impacting poly-GA aggregates. Single nucleus
                      transcriptomics indicated that CD primarily affected
                      oligodendrocytes, significantly restored myelin gene
                      expression, increased density of myelinated axons, inhibited
                      the disease-associated oligodendrocyte response, and
                      downregulated the lipid-associated genes Plin4 and ApoD.
                      These results suggest that reducing excess free cholesterol
                      in the CNS could be a viable ALS treatment strategy.”
                      Overall design: GA-Nes mice (LaClair et al, Acta
                      Neuropathologica 2020) and littermate controls were treated
                      with the cholesterol sequestering drug
                      2-hydroxypropyl-β-cyclodextrin (CD) or vehicle control from
                      P21 (daily subcutaneous treatment) and harvested on P40. We
                      aim to investigate the mechanisms of lifespan extension and
                      neurofilament reduction with CD treatment in female mice.
                      Includes 15 samples.},
      cin          = {AG Edbauer},
      cid          = {I:(DE-2719)1110004},
      pnm          = {352 - Disease Mechanisms (POF4-352)},
      pid          = {G:(DE-HGF)POF4-352},
      typ          = {PUB:(DE-HGF)32},
      url          = {https://pub.dzne.de/record/277510},
}