Movement disorders : official journal of the Movement Disorder Society · 2025
Patient-Derived Neurons Exhibit α-Synuclein Pathology and Previously Unrecognized Major Histocompatibility Complex Class I Elevation in Mitochondrial Membrane Protein-Associated Neurodegeneration.
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Heger Leonie M, Kertess Leonie, Kaufhold Clara, Gubinelli Francesco, Cardona-Alberich Aida, Özata Gamze, Müller Stephan A, Tschirner Sarah K, Stehling Oliver, Schifferer Martina, Peron Camille, Tiranti Valeria, Lill Roland, Iuso Arcangela, Zecca Luigi, Strupp Michael, Oertel Wolfgang, Lichtenthaler Stefan F, Burbulla Lena F
Аннотация
BACKGROUND: Mitochondrial 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.
OBJECTIVE: The mechanisms driving neuron vulnerability remain unclear. Our study aimed to develop a patient-derived disease model replicating key pathologies of patient brains.
METHODS: We generated induced pluripotent stem cell-derived midbrain dopaminergic neurons from MPAN patients and examined ultrastructural and biochemical markers of pathology.
RESULTS: MPAN 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.
CONCLUSIONS: This 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.
OBJECTIVE: The mechanisms driving neuron vulnerability remain unclear. Our study aimed to develop a patient-derived disease model replicating key pathologies of patient brains.
METHODS: We generated induced pluripotent stem cell-derived midbrain dopaminergic neurons from MPAN patients and examined ultrastructural and biochemical markers of pathology.
RESULTS: MPAN 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.
CONCLUSIONS: This 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.