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Heger, L.M.* ; Kertess, L.* ; Kaufhold, C.* ; Gubinelli, F.* ; Cardona-Alberich, A.* ; Özata, G.* ; Müller, S.A.* ; Tschirner, S.K.* ; Stehling, O.* ; Schifferer, M.* ; Peron, C.* ; Tiranti, V.* ; Lill, R.* ; Iuso, A. ; Zecca, L.* ; Strupp, M.* ; Oertel, W.H. ; Lichtenthaler, S.F.* ; Burbulla, L.F.*

Patient-derived neurons exhibit α-synuclein pathology and previously unrecognized major histocompatibility complex class I elevation in mitochondrial membrane protein-associated neurodegeneration.

Mov. Disord., DOI: 10.1002/mds.70029 (2025)
Publ. Version/Full Text Research data DOI PMC
Open Access Hybrid
Creative Commons Lizenzvertrag
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.
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Publication type Article: Journal article
Document type Scientific Article
Keywords Mpan ; Nbia ; Dopaminergic Neurons ; Ipsc Disease Modeling ; α‐synuclein; Parkinsons-disease; Substantia-nigra; Iron; Aggregation; Oxidation; C19orf12; Subtype
Language english
Publication Year 2025
HGF-reported in Year 2025
ISSN (print) / ISBN 0885-3185
e-ISSN 1531-8257
Journal Movement Disorders
Publisher Wiley
Publishing Place 111 River St, Hoboken 07030-5774, Nj Usa
Reviewing status Peer reviewed
Institute(s) Institute of Neurogenomics (ING)
POF-Topic(s) 30205 - Bioengineering and Digital Health
Research field(s) Genetics and Epidemiology
PSP Element(s) G-503200-001
Grants NBIA Suisse
NBIA Disorders Association (NBIADA, USA), Associazione Italiana Sindromi Neurodegenerative da Accumulo di Ferro (AISNAF, Italy), Hoffnungsbaum e.V. (HoBa, Germany), and Stichting Ijzersterk (The Netherlands)
Mariani Foundation
Pezzoli Foundation for Parkinson's Disease
Linea Azione 4.1; T4-AN-09 of the Italian Ministry of health, project POS
DOI 10.1002/mds.70029
WOS ID 001570888500001
Scopus ID 105016258135
PubMed ID 40948186
Erfassungsdatum 2025-11-04
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