TY  - JOUR
AU  - Efendic, Fatima
AU  - Hermann, Andreas
AU  - Frech, Moritz J
TI  - Disrupted Myelination in FAHN: Insights from a Patient-Specific hiPSC Neuron-Oligodendrocyte Model.
JO  - Cells
VL  - 14
IS  - 16
SN  - 2073-4409
CY  - Basel
PB  - MDPI
M1  - DZNE-2025-00991
SP  - 1261
PY  - 2025
AB  - 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.
KW  - Humans
KW  - Induced Pluripotent Stem Cells: metabolism
KW  - Induced Pluripotent Stem Cells: pathology
KW  - Myelin Sheath: metabolism
KW  - Myelin Sheath: pathology
KW  - Neurons: metabolism
KW  - Neurons: pathology
KW  - Oligodendroglia: metabolism
KW  - Oligodendroglia: pathology
KW  - Autophagy
KW  - Models, Biological
KW  - Neurodegenerative Diseases: pathology
KW  - Neurodegenerative Diseases: genetics
KW  - Neurodegenerative Diseases: metabolism
KW  - Mutation: genetics
KW  - Mixed Function Oxygenases: genetics
KW  - Mixed Function Oxygenases: metabolism
KW  - Coculture Techniques
KW  - FA2H (Other)
KW  - FAHN (Other)
KW  - autophagy (Other)
KW  - demyelination (Other)
KW  - induced pluripotent stem cells (Other)
KW  - myelin proteins (Other)
KW  - neurons (Other)
KW  - oligodendrocytes (Other)
KW  - Mixed Function Oxygenases (NLM Chemicals)
LB  - PUB:(DE-HGF)16
C6  - pmid:40862740
C2  - pmc:PMC12384766
DO  - DOI:10.3390/cells14161261
UR  - https://pub.dzne.de/record/280907
ER  -