Journal Article

DZNE-2026-00187

http://join2-wiki.gsi.de/foswiki/pub/Main/Artwork/join2_logo100x88.png VMAT2 dysfunction impairs vesicular dopamine uptake, driving its oxidation and α-synuclein pathology in DJ-1-linked Parkinson's neurons.

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

2026
Assoc. Washington, DC [u.a.]

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Please use a persistent id in citations: doi:10.1126/sciadv.adz5645

Abstract: 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.

Keyword(s): Vesicular Monoamine Transport Proteins: metabolism (MeSH) ; Vesicular Monoamine Transport Proteins: genetics (MeSH) ; Dopamine: metabolism (MeSH) ; Parkinson Disease: metabolism (MeSH) ; Parkinson Disease: pathology (MeSH) ; Parkinson Disease: genetics (MeSH) ; Protein Deglycase DJ-1: genetics (MeSH) ; Protein Deglycase DJ-1: metabolism (MeSH) ; Humans (MeSH) ; Dopaminergic Neurons: metabolism (MeSH) ; Dopaminergic Neurons: pathology (MeSH) ; alpha-Synuclein: metabolism (MeSH) ; alpha-Synuclein: genetics (MeSH) ; Oxidation-Reduction (MeSH) ; Animals (MeSH) ; Synaptic Vesicles: metabolism (MeSH) ; Mice (MeSH) ; Adenosine Triphosphate: metabolism (MeSH) ; Induced Pluripotent Stem Cells: metabolism (MeSH) ; Mesencephalon: metabolism (MeSH) ; Vesicular Monoamine Transport Proteins ; Dopamine ; Protein Deglycase DJ-1 ; alpha-Synuclein ; SLC18A2 protein, human ; Adenosine Triphosphate ; PARK7 protein, human

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Contributing Institute(s):

1. Translational Disease Modeling (AG Burbulla)
2. Neuroproteomics (AG Lichtenthaler)
3. Neuronal Cell Biology (AG Misgeld)
4. Genome Engineering (AG Wurst)

Research Program(s):

1. 352 - Disease Mechanisms (POF4-352) (POF4-352)
2. 351 - Brain Function (POF4-351) (POF4-351)

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