TY  - JOUR
AU  - Heger, Leonie
AU  - Kertess, Leonie
AU  - Kaufhold, Clara Margarete
AU  - Gubinelli, Francesco
AU  - Cardona-Alberich, Aida
AU  - Özata, Gamze
AU  - Müller, Stephan A
AU  - Tschirner, Sarah K
AU  - Stehling, Oliver
AU  - Schifferer, Martina
AU  - Peron, Camille
AU  - Tiranti, Valeria
AU  - Lill, Roland
AU  - Iuso, Arcangela
AU  - Zecca, Luigi
AU  - Strupp, Michael
AU  - Oertel, Wolfgang
AU  - Lichtenthaler, Stefan F
AU  - Burbulla, Lena F.
TI  - Patient-Derived Neurons Exhibit α-Synuclein Pathology and Previously Unrecognized Major Histocompatibility Complex Class I Elevation in Mitochondrial Membrane Protein-Associated Neurodegeneration.
JO  - Movement disorders
VL  - 40
IS  - 12
SN  - 0885-3185
CY  - New York, NY
PB  - Wiley
M1  - DZNE-2025-01377
SP  - 2811 - 2818
PY  - 2025
AB  - 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.The mechanisms driving neuron vulnerability remain unclear. Our study aimed to develop a patient-derived disease model replicating key pathologies of patient brains.We generated induced pluripotent stem cell-derived midbrain dopaminergic neurons from MPAN patients and examined ultrastructural and biochemical markers of pathology.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.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.
KW  - MPAN (Other)
KW  - NBIA (Other)
KW  - dopaminergic neurons (Other)
KW  - iPSC disease modeling (Other)
KW  - α‐synuclein (Other)
LB  - PUB:(DE-HGF)16
C6  - pmid:40948186
DO  - DOI:10.1002/mds.70029
UR  - https://pub.dzne.de/record/282916
ER  -