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Heger, L.M.* ; Gubinelli, F.* ; Huber, A.J.* ; Cardona-Alberich, A.* ; Rovere, M.* ; Matti, U.* ; Müller, S.A.* ; Nagaraja, S.R.* ; Jaschkowitz, L.* ; Schifferer, M.* ; Wurst, W. ; Lichtenthaler, S.F.* ; Behrends, C.* ; Sambandan, S.* ; Burbulla, L.F.*

VMAT2 dysfunction impairs vesicular dopamine uptake, driving its oxidation and α-synuclein pathology in DJ-1-linked Parkinson's neurons.

Sci. Adv. 12:eadz5645 (2026)
Verlagsversion Forschungsdaten DOI PMC
Open Access Gold
Creative Commons Lizenzvertrag
Parkinson's disease (PD) is characterized by α-synuclein accumulation and dopaminergic neuron degeneration, with dopamine (DA) oxidation emerging as a key pathological driver. However, the mechanisms underlying this neurotoxic process remain unclear. Using PD patient-derived and CRISPR-engineered induced pluripotent stem cell midbrain dopaminergic neurons lacking DJ-1, we identified defective sequestration of cytosolic DA into synaptic vesicles, which culminated in DA oxidation and α-synuclein pathology. In-depth proteomics, state-of-the-art imaging, and ultrasensitive DA probes uncovered that decreased vesicular monoamine transporter 2 (VMAT2) protein and function impaired vesicular DA uptake, resulting in reduced vesicle availability and abnormal vesicle morphology. Furthermore, VMAT2 activity and vesicle endocytosis are processes dependent on adenosine 5'-triphosphate (ATP), which is notably reduced in DJ-1-deficient dopaminergic neurons. ATP supplementation restored vesicular function and alleviated DA-related pathologies in mutant dopaminergic neurons. This study reveals an ATP-sensitive mechanism that regulates DA homeostasis through VMAT2 and vesicle dynamics in midbrain dopaminergic neurons, highlighting enhanced DA sequestration as a promising therapeutic strategy for PD.
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Publikationstyp Artikel: Journalartikel
Dokumenttyp Wissenschaftlicher Artikel
Schlagwörter Vesicular Monoamine Transporter 2 ; Dopaminergic ; Dopamine ; Vesicular Monoamine Transporter ; Vesicular Transport Protein ; Neurodegeneration ; Synaptic Vesicle ; Monoamine Neurotransmitter; Monoamine Transporter-2; Lysosomal Dysfunction; Integrative Analysis; Dj-1-deficient Mice; Synaptic Vesicles; Substantia-nigra; Disease; Dj-1; Mitochondrial; Neuromelanin
ISSN (print) / ISBN 2375-2548
e-ISSN 2375-2548
Zeitschrift Science Advances
Quellenangaben Band: 12, Heft: 7, Seiten: , Artikelnummer: eadz5645 Supplement: ,
Verlag American Association for the Advancement of Science (AAAS)
Verlagsort Washington, DC [u.a.]
Begutachtungsstatus Peer reviewed
Institut(e) Institute of Stem Cell Research (ISF)
Förderungen Helmholtz Association
Bundesministerium fur Bildung und Forschung (BMBF)
German Research Foundation)
Deutsche Forschungsgemeinschaft (DFG
Rise up! programme of the Boehringer Ingelheim Foundation (BIS)
European Research Council (ERC)