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BackgroundMitochondrial membrane protein-associated neurodegeneration (MPAN) from the neurodegeneration with brain iron accumulation (NBIA) family is a rare neurodegenerative disease marked by α-synuclein aggregation, brain iron accumulation, and midbrain dopaminergic neuron degeneration.ObjectiveThe mechanisms driving neuron vulnerability remain unclear. Our study aimed to develop a patient-derived disease model replicating key pathologies of patient brains.MethodsWe generated induced pluripotent stem cell-derived midbrain dopaminergic neurons from MPAN patients and examined ultrastructural and biochemical markers of pathology.ResultsMPAN patient neurons displayed α-synuclein aggregation, axonal swellings, iron accumulation, and severe membrane destruction. In addition, levels of the major histocompatibility complex class I (MHC-I), linked to cellular stress and neurodegenerative processes, were elevated in patient neurons. Treatment with acetyl-leucine, a potentially neuroprotective compound, decreased MHC-I.ConclusionsThis first patient-derived neuronal model of MPAN provides a useful tool for further research aimed at unraveling the complexities of this disease and developing potential therapeutic interventions. © 2025 The Author(s). Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.
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