000282916 001__ 282916 000282916 005__ 20251217170444.0 000282916 0247_ $$2doi$$a10.1002/mds.70029 000282916 0247_ $$2pmid$$apmid:40948186 000282916 0247_ $$2ISSN$$a0885-3185 000282916 0247_ $$2ISSN$$a1531-8257 000282916 037__ $$aDZNE-2025-01377 000282916 041__ $$aEnglish 000282916 082__ $$a610 000282916 1001_ $$0P:(DE-2719)9001931$$aHeger, Leonie$$b0$$udzne 000282916 245__ $$aPatient-Derived Neurons Exhibit α-Synuclein Pathology and Previously Unrecognized Major Histocompatibility Complex Class I Elevation in Mitochondrial Membrane Protein-Associated Neurodegeneration. 000282916 260__ $$aNew York, NY$$bWiley$$c2025 000282916 3367_ $$2DRIVER$$aarticle 000282916 3367_ $$2DataCite$$aOutput Types/Journal article 000282916 3367_ $$0PUB:(DE-HGF)16$$2PUB:(DE-HGF)$$aJournal Article$$bjournal$$mjournal$$s1765977544_5351 000282916 3367_ $$2BibTeX$$aARTICLE 000282916 3367_ $$2ORCID$$aJOURNAL_ARTICLE 000282916 3367_ $$00$$2EndNote$$aJournal Article 000282916 520__ $$aMitochondrial membrane protein-associated neurodegeneration (MPAN) from the neurodegeneration with brain iron accumulation (NBIA) family is a rare neurodegenerative disease marked by α-synuclein aggregation, brain iron accumulation, and midbrain dopaminergic neuron degeneration.The mechanisms driving neuron vulnerability remain unclear. Our study aimed to develop a patient-derived disease model replicating key pathologies of patient brains.We generated induced pluripotent stem cell-derived midbrain dopaminergic neurons from MPAN patients and examined ultrastructural and biochemical markers of pathology.MPAN patient neurons displayed α-synuclein aggregation, axonal swellings, iron accumulation, and severe membrane destruction. In addition, levels of the major histocompatibility complex class I (MHC-I), linked to cellular stress and neurodegenerative processes, were elevated in patient neurons. Treatment with acetyl-leucine, a potentially neuroprotective compound, decreased MHC-I.This first patient-derived neuronal model of MPAN provides a useful tool for further research aimed at unraveling the complexities of this disease and developing potential therapeutic interventions. © 2025 The Author(s). Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society. 000282916 536__ $$0G:(DE-HGF)POF4-352$$a352 - Disease Mechanisms (POF4-352)$$cPOF4-352$$fPOF IV$$x0 000282916 536__ $$0G:(DE-HGF)POF4-351$$a351 - Brain Function (POF4-351)$$cPOF4-351$$fPOF IV$$x1 000282916 588__ $$aDataset connected to CrossRef, PubMed, , Journals: pub.dzne.de 000282916 650_7 $$2Other$$aMPAN 000282916 650_7 $$2Other$$aNBIA 000282916 650_7 $$2Other$$adopaminergic neurons 000282916 650_7 $$2Other$$aiPSC disease modeling 000282916 650_7 $$2Other$$aα‐synuclein 000282916 7001_ $$aKertess, Leonie$$b1 000282916 7001_ $$0P:(DE-2719)9002163$$aKaufhold, Clara Margarete$$b2$$udzne 000282916 7001_ $$0P:(DE-2719)9002293$$aGubinelli, Francesco$$b3$$udzne 000282916 7001_ $$aCardona-Alberich, Aida$$b4 000282916 7001_ $$aÖzata, Gamze$$b5 000282916 7001_ $$0P:(DE-2719)2810938$$aMüller, Stephan A$$b6 000282916 7001_ $$0P:(DE-2719)9000794$$aTschirner, Sarah K$$b7$$udzne 000282916 7001_ $$aStehling, Oliver$$b8 000282916 7001_ $$0P:(DE-2719)2812260$$aSchifferer, Martina$$b9$$udzne 000282916 7001_ $$aPeron, Camille$$b10 000282916 7001_ $$aTiranti, Valeria$$b11 000282916 7001_ $$aLill, Roland$$b12 000282916 7001_ $$aIuso, Arcangela$$b13 000282916 7001_ $$aZecca, Luigi$$b14 000282916 7001_ $$aStrupp, Michael$$b15 000282916 7001_ $$0P:(DE-2719)9000908$$aOertel, Wolfgang$$b16 000282916 7001_ $$0P:(DE-2719)2181459$$aLichtenthaler, Stefan F$$b17$$udzne 000282916 7001_ $$0P:(DE-2719)9000040$$aBurbulla, Lena F.$$b18$$eLast author$$udzne 000282916 773__ $$0PERI:(DE-600)2041249-6$$a10.1002/mds.70029$$gVol. 40, no. 12, p. 2811 - 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