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@ARTICLE{Heger:282916,
author = {Heger, Leonie and Kertess, Leonie and Kaufhold, Clara
Margarete and Gubinelli, Francesco and Cardona-Alberich,
Aida and Özata, Gamze and Müller, Stephan A and Tschirner,
Sarah K and Stehling, Oliver and Schifferer, Martina and
Peron, Camille and Tiranti, Valeria and Lill, Roland and
Iuso, Arcangela and Zecca, Luigi and Strupp, Michael and
Oertel, Wolfgang and Lichtenthaler, Stefan F and Burbulla,
Lena F.},
title = {{P}atient-{D}erived {N}eurons {E}xhibit α-{S}ynuclein
{P}athology and {P}reviously {U}nrecognized {M}ajor
{H}istocompatibility {C}omplex {C}lass {I} {E}levation in
{M}itochondrial {M}embrane {P}rotein-{A}ssociated
{N}eurodegeneration.},
journal = {Movement disorders},
volume = {40},
number = {12},
issn = {0885-3185},
address = {New York, NY},
publisher = {Wiley},
reportid = {DZNE-2025-01377},
pages = {2811 - 2818},
year = {2025},
abstract = {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.},
keywords = {MPAN (Other) / NBIA (Other) / dopaminergic neurons (Other)
/ iPSC disease modeling (Other) / α‐synuclein (Other)},
cin = {AG Burbulla / AG Lichtenthaler / AG Misgeld},
ddc = {610},
cid = {I:(DE-2719)5000074 / I:(DE-2719)1110006 /
I:(DE-2719)1110000-4},
pnm = {352 - Disease Mechanisms (POF4-352) / 351 - Brain Function
(POF4-351)},
pid = {G:(DE-HGF)POF4-352 / G:(DE-HGF)POF4-351},
typ = {PUB:(DE-HGF)16},
pubmed = {pmid:40948186},
doi = {10.1002/mds.70029},
url = {https://pub.dzne.de/record/282916},
}