Journal Article

DZNE-2025-00991

http://join2-wiki.gsi.de/foswiki/pub/Main/Artwork/join2_logo100x88.png Disrupted Myelination in FAHN: Insights from a Patient-Specific hiPSC Neuron-Oligodendrocyte Model.

Efendic, F. ; Hermann, A.DZNE* ; Frech, M. J.

2025
MDPI Basel

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Please use a persistent id in citations: doi:10.3390/cells14161261

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.

Keyword(s): Humans (MeSH) ; Induced Pluripotent Stem Cells: metabolism (MeSH) ; Induced Pluripotent Stem Cells: pathology (MeSH) ; Myelin Sheath: metabolism (MeSH) ; Myelin Sheath: pathology (MeSH) ; Neurons: metabolism (MeSH) ; Neurons: pathology (MeSH) ; Oligodendroglia: metabolism (MeSH) ; Oligodendroglia: pathology (MeSH) ; Autophagy (MeSH) ; Models, Biological (MeSH) ; Neurodegenerative Diseases: pathology (MeSH) ; Neurodegenerative Diseases: genetics (MeSH) ; Neurodegenerative Diseases: metabolism (MeSH) ; Mutation: genetics (MeSH) ; Mixed Function Oxygenases: genetics (MeSH) ; Mixed Function Oxygenases: metabolism (MeSH) ; Coculture Techniques (MeSH) ; FA2H ; FAHN ; autophagy ; demyelination ; induced pluripotent stem cells ; myelin proteins ; neurons ; oligodendrocytes ; Mixed Function Oxygenases

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Contributing Institute(s):

1. Translational Neurodegeneration (AG Hermann)

Research Program(s):

1. 353 - Clinical and Health Care Research (POF4-353) (POF4-353)

Appears in the scientific report 2025

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