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@ARTICLE{Rezaei:277990,
      author       = {Rezaei, Ali and Kocsis-Jutka, Virág and Günes, Zeynep
                      Irem and Zeng, Qing and Kislinger, Georg and Bauernschmitt,
                      Franz and Isilgan, Huseyin Berkcan and Parisi, Laura R and
                      Kaya, Tugberk and Franzenburg, Sören and Koppenbrink, Jonas
                      and Knogler, Julia and Arzberger, Thomas and Farny, Daniel
                      and Nuscher, Brigitte and Katona, Eszter and Dhingra,
                      Ashutosh and Yang, Chao and Gouna, Garyfallia and LaClair,
                      Katherine and Janjic, Aleksandar and Enard, Wolfgang and
                      Zhou, Qihui and Hagan, Nellwyn and Ofengeim, Dimitry and
                      Beltrán, Eduardo and Gökce, Ozgun and Simons, Mikael and
                      Liebscher, Sabine and Edbauer, Dieter},
      title        = {{C}orrection of dysregulated lipid metabolism normalizes
                      gene expression in oligodendrocytes and prolongs lifespan in
                      female poly-{GA} {C}9orf72 mice.},
      journal      = {Nature Communications},
      volume       = {16},
      number       = {1},
      issn         = {2041-1723},
      address      = {[London]},
      publisher    = {Springer Nature},
      reportid     = {DZNE-2025-00517},
      pages        = {3442},
      year         = {2025},
      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-Camk2a 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.},
      keywords     = {Animals / Female / Mice / Oligodendroglia: metabolism /
                      Oligodendroglia: drug effects / Lipid Metabolism: drug
                      effects / Lipid Metabolism: genetics / Amyotrophic Lateral
                      Sclerosis: genetics / Amyotrophic Lateral Sclerosis:
                      metabolism / Amyotrophic Lateral Sclerosis: drug therapy /
                      Amyotrophic Lateral Sclerosis: pathology / C9orf72 Protein:
                      genetics / C9orf72 Protein: metabolism / Disease Models,
                      Animal / Male / Cholesterol: metabolism / Humans /
                      2-Hydroxypropyl-beta-cyclodextrin: pharmacology / Mice,
                      Transgenic / Myelin Sheath: metabolism / Spinal Cord:
                      metabolism / Spinal Cord: pathology / Longevity: drug
                      effects / Longevity: genetics / C9orf72 Protein (NLM
                      Chemicals) / Cholesterol (NLM Chemicals) /
                      2-Hydroxypropyl-beta-cyclodextrin (NLM Chemicals)},
      cin          = {AG Edbauer / AG Simons / AG Zhou},
      ddc          = {500},
      cid          = {I:(DE-2719)1110004 / I:(DE-2719)1110008 /
                      I:(DE-2719)5000080},
      pnm          = {352 - Disease Mechanisms (POF4-352) / 351 - Brain Function
                      (POF4-351)},
      pid          = {G:(DE-HGF)POF4-352 / G:(DE-HGF)POF4-351},
      typ          = {PUB:(DE-HGF)16},
      pubmed       = {pmid:40216746},
      pmc          = {pmc:PMC11992041},
      doi          = {10.1038/s41467-025-58634-4},
      url          = {https://pub.dzne.de/record/277990},
}