2026-02-24 ミュンヘン大学(LMU)
<関連情報>
- https://www.lmu.de/en/newsroom/news-overview/news/dysfunctional-packaging-of-dopamine-advances-symptoms-of-parkinsons-disease-b3fb945c.html
- https://www.science.org/doi/10.1126/sciadv.adz5645
VMAT2の機能不全は小胞ドーパミンの取り込みを阻害し、DJ-1関連パーキンソン病ニューロンにおけるドーパミンの酸化とα-シヌクレイン病理を促進する VMAT2 dysfunction impairs vesicular dopamine uptake, driving its oxidation and α-synuclein pathology in DJ-1–linked Parkinson’s neurons
Leonie M. Heger, Francesco Gubinelli, Andreas J. Huber, Aida Cardona-Alberich, […] , and Lena F. Burbulla
Science Advances Published:11 Feb 2026
DOI:https://doi.org/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.
