%0 Journal Article
%A Heger, Leonie
%A Gubinelli, Francesco
%A Huber, Andreas J
%A Cardona-Alberich, Aida
%A Rovere, Matteo
%A Matti, Ulf
%A Müller, Stephan A
%A Nagaraja, Sankarshana
%A Jaschkowitz, Lena
%A Schifferer, Martina
%A Wurst, Wolfgang
%A Lichtenthaler, Stefan F
%A Behrends, Christian
%A Sambandan, Sivakumar
%A Burbulla, Lena F.
%T VMAT2 dysfunction impairs vesicular dopamine uptake, driving its oxidation and α-synuclein pathology in DJ-1-linked Parkinson's neurons.
%J Science advances
%V 12
%N 7
%@ 2375-2548
%C Washington, DC [u.a.]
%I Assoc.
%M DZNE-2026-00187
%P eadz5645
%D 2026
%X 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.
%K Vesicular Monoamine Transport Proteins: metabolism
%K Vesicular Monoamine Transport Proteins: genetics
%K Dopamine: metabolism
%K Parkinson Disease: metabolism
%K Parkinson Disease: pathology
%K Parkinson Disease: genetics
%K Protein Deglycase DJ-1: genetics
%K Protein Deglycase DJ-1: metabolism
%K Humans
%K Dopaminergic Neurons: metabolism
%K Dopaminergic Neurons: pathology
%K alpha-Synuclein: metabolism
%K alpha-Synuclein: genetics
%K Oxidation-Reduction
%K Animals
%K Synaptic Vesicles: metabolism
%K Mice
%K Adenosine Triphosphate: metabolism
%K Induced Pluripotent Stem Cells: metabolism
%K Mesencephalon: metabolism
%K Vesicular Monoamine Transport Proteins (NLM Chemicals)
%K Dopamine (NLM Chemicals)
%K Protein Deglycase DJ-1 (NLM Chemicals)
%K alpha-Synuclein (NLM Chemicals)
%K SLC18A2 protein, human (NLM Chemicals)
%K Adenosine Triphosphate (NLM Chemicals)
%K PARK7 protein, human (NLM Chemicals)
%F PUB:(DE-HGF)16
%9 Journal Article
%$ pmid:41671379
%2 pmc:PMC12893317
%R 10.1126/sciadv.adz5645
%U https://pub.dzne.de/record/285208