TY  - JOUR
AU  - Heger, Leonie
AU  - Gubinelli, Francesco
AU  - Huber, Andreas J
AU  - Cardona-Alberich, Aida
AU  - Rovere, Matteo
AU  - Matti, Ulf
AU  - Müller, Stephan A
AU  - Nagaraja, Sankarshana
AU  - Jaschkowitz, Lena
AU  - Schifferer, Martina
AU  - Wurst, Wolfgang
AU  - Lichtenthaler, Stefan F
AU  - Behrends, Christian
AU  - Sambandan, Sivakumar
AU  - Burbulla, Lena F.
TI  - VMAT2 dysfunction impairs vesicular dopamine uptake, driving its oxidation and α-synuclein pathology in DJ-1-linked Parkinson's neurons.
JO  - Science advances
VL  - 12
IS  - 7
SN  - 2375-2548
CY  - Washington, DC [u.a.]
PB  - Assoc.
M1  - DZNE-2026-00187
SP  - eadz5645
PY  - 2026
AB  - 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.
KW  - Vesicular Monoamine Transport Proteins: metabolism
KW  - Vesicular Monoamine Transport Proteins: genetics
KW  - Dopamine: metabolism
KW  - Parkinson Disease: metabolism
KW  - Parkinson Disease: pathology
KW  - Parkinson Disease: genetics
KW  - Protein Deglycase DJ-1: genetics
KW  - Protein Deglycase DJ-1: metabolism
KW  - Humans
KW  - Dopaminergic Neurons: metabolism
KW  - Dopaminergic Neurons: pathology
KW  - alpha-Synuclein: metabolism
KW  - alpha-Synuclein: genetics
KW  - Oxidation-Reduction
KW  - Animals
KW  - Synaptic Vesicles: metabolism
KW  - Mice
KW  - Adenosine Triphosphate: metabolism
KW  - Induced Pluripotent Stem Cells: metabolism
KW  - Mesencephalon: metabolism
KW  - Vesicular Monoamine Transport Proteins (NLM Chemicals)
KW  - Dopamine (NLM Chemicals)
KW  - Protein Deglycase DJ-1 (NLM Chemicals)
KW  - alpha-Synuclein (NLM Chemicals)
KW  - SLC18A2 protein, human (NLM Chemicals)
KW  - Adenosine Triphosphate (NLM Chemicals)
KW  - PARK7 protein, human (NLM Chemicals)
LB  - PUB:(DE-HGF)16
C6  - pmid:41671379
C2  - pmc:PMC12893317
DO  - DOI:10.1126/sciadv.adz5645
UR  - https://pub.dzne.de/record/285208
ER  -