Disrupted Myelination in FAHN: Insights from a Patient-Specific hiPSC Neuron–Oligodendrocyte Model

Fatty-acid-hydroxylase-associated neurodegeneration (FAHN) is a rare neurodegenerative disorder caused by loss-of-function mutations in the <i>FA2H</i> 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 <i>FA2H</i> mutations compromise both the structural integrity of myelin and the efficiency of the autophagic machinery, highlighting potential targets for future therapeutic interventions.