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@ARTICLE{Efendic:280907,
      author       = {Efendic, Fatima and Hermann, Andreas and Frech, Moritz J},
      title        = {{D}isrupted {M}yelination in {FAHN}: {I}nsights from a
                      {P}atient-{S}pecific hi{PSC} {N}euron-{O}ligodendrocyte
                      {M}odel.},
      journal      = {Cells},
      volume       = {14},
      number       = {16},
      issn         = {2073-4409},
      address      = {Basel},
      publisher    = {MDPI},
      reportid     = {DZNE-2025-00991},
      pages        = {1261},
      year         = {2025},
      abstract     = {Fatty-acid-hydroxylase-associated neurodegeneration (FAHN)
                      is a rare neurodegenerative disorder caused by
                      loss-of-function mutations in the FA2H gene, leading to
                      impaired enzymatic activity and resulting in myelin sheath
                      instability, demyelination, and axonal degeneration. In this
                      study, we established a human in vitro model using neurons
                      and oligodendrocytes derived from induced pluripotent stem
                      cells (hiPSCs) of a FAHN patient. This coculture system
                      enabled the investigation of myelination processes and
                      myelin integrity in a disease-relevant context. Analyses
                      using immunofluorescence and Western blot revealed impaired
                      expression and localisation of key myelin proteins in
                      oligodendrocytes and cocultures. FA2H-deficient cells showed
                      reduced myelination, shortened internodes, and disrupted
                      formation of the nodes of Ranvier. Additionally, we
                      identified autophagy defects-a hallmark of many
                      neurodegenerative diseases-including reduced p62 expression,
                      elevated LC3B levels, and impaired fusion of autophagosomes
                      with lysosomes. This study presents a robust hiPSC-based
                      model to study FAHN, offering new insights into the
                      molecular pathology of the disease. Our findings suggest
                      that FA2H mutations compromise both the structural integrity
                      of myelin and the efficiency of the autophagic machinery,
                      highlighting potential targets for future therapeutic
                      interventions.},
      keywords     = {Humans / Induced Pluripotent Stem Cells: metabolism /
                      Induced Pluripotent Stem Cells: pathology / Myelin Sheath:
                      metabolism / Myelin Sheath: pathology / Neurons: metabolism
                      / Neurons: pathology / Oligodendroglia: metabolism /
                      Oligodendroglia: pathology / Autophagy / Models, Biological
                      / Neurodegenerative Diseases: pathology / Neurodegenerative
                      Diseases: genetics / Neurodegenerative Diseases: metabolism
                      / Mutation: genetics / Mixed Function Oxygenases: genetics /
                      Mixed Function Oxygenases: metabolism / Coculture Techniques
                      / FA2H (Other) / FAHN (Other) / autophagy (Other) /
                      demyelination (Other) / induced pluripotent stem cells
                      (Other) / myelin proteins (Other) / neurons (Other) /
                      oligodendrocytes (Other) / Mixed Function Oxygenases (NLM
                      Chemicals)},
      cin          = {AG Hermann},
      ddc          = {570},
      cid          = {I:(DE-2719)1511100},
      pnm          = {353 - Clinical and Health Care Research (POF4-353)},
      pid          = {G:(DE-HGF)POF4-353},
      typ          = {PUB:(DE-HGF)16},
      pubmed       = {pmid:40862740},
      pmc          = {pmc:PMC12384766},
      doi          = {10.3390/cells14161261},
      url          = {https://pub.dzne.de/record/280907},
}