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000285208 1001_ $$0P:(DE-2719)9001931$$aHeger, Leonie$$b0$$udzne
000285208 245__ $$aVMAT2 dysfunction impairs vesicular dopamine uptake, driving its oxidation and α-synuclein pathology in DJ-1-linked Parkinson's neurons.
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000285208 520__ $$aParkinson'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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000285208 650_7 $$2NLM Chemicals$$aVesicular Monoamine Transport Proteins
000285208 650_7 $$0VTD58H1Z2X$$2NLM Chemicals$$aDopamine
000285208 650_7 $$0EC 3.1.2.-$$2NLM Chemicals$$aProtein Deglycase DJ-1
000285208 650_7 $$2NLM Chemicals$$aalpha-Synuclein
000285208 650_7 $$2NLM Chemicals$$aSLC18A2 protein, human
000285208 650_7 $$08L70Q75FXE$$2NLM Chemicals$$aAdenosine Triphosphate
000285208 650_7 $$0EC 3.1.2.-$$2NLM Chemicals$$aPARK7 protein, human
000285208 650_2 $$2MeSH$$aVesicular Monoamine Transport Proteins: metabolism
000285208 650_2 $$2MeSH$$aVesicular Monoamine Transport Proteins: genetics
000285208 650_2 $$2MeSH$$aDopamine: metabolism
000285208 650_2 $$2MeSH$$aParkinson Disease: metabolism
000285208 650_2 $$2MeSH$$aParkinson Disease: pathology
000285208 650_2 $$2MeSH$$aParkinson Disease: genetics
000285208 650_2 $$2MeSH$$aProtein Deglycase DJ-1: genetics
000285208 650_2 $$2MeSH$$aProtein Deglycase DJ-1: metabolism
000285208 650_2 $$2MeSH$$aHumans
000285208 650_2 $$2MeSH$$aDopaminergic Neurons: metabolism
000285208 650_2 $$2MeSH$$aDopaminergic Neurons: pathology
000285208 650_2 $$2MeSH$$aalpha-Synuclein: metabolism
000285208 650_2 $$2MeSH$$aalpha-Synuclein: genetics
000285208 650_2 $$2MeSH$$aOxidation-Reduction
000285208 650_2 $$2MeSH$$aAnimals
000285208 650_2 $$2MeSH$$aSynaptic Vesicles: metabolism
000285208 650_2 $$2MeSH$$aMice
000285208 650_2 $$2MeSH$$aAdenosine Triphosphate: metabolism
000285208 650_2 $$2MeSH$$aInduced Pluripotent Stem Cells: metabolism
000285208 650_2 $$2MeSH$$aMesencephalon: metabolism
000285208 7001_ $$0P:(DE-2719)9002293$$aGubinelli, Francesco$$b1$$udzne
000285208 7001_ $$aHuber, Andreas J$$b2
000285208 7001_ $$00009-0009-1852-5941$$aCardona-Alberich, Aida$$b3
000285208 7001_ $$0P:(DE-2719)9003064$$aRovere, Matteo$$b4$$udzne
000285208 7001_ $$00000-0001-5548-1081$$aMatti, Ulf$$b5
000285208 7001_ $$0P:(DE-2719)2810938$$aMüller, Stephan A$$b6
000285208 7001_ $$0P:(DE-2719)9003126$$aNagaraja, Sankarshana$$b7$$udzne
000285208 7001_ $$00009-0007-9022-0726$$aJaschkowitz, Lena$$b8
000285208 7001_ $$0P:(DE-2719)2812260$$aSchifferer, Martina$$b9
000285208 7001_ $$0P:(DE-2719)2000028$$aWurst, Wolfgang$$b10
000285208 7001_ $$0P:(DE-2719)2181459$$aLichtenthaler, Stefan F$$b11
000285208 7001_ $$00000-0002-9184-7607$$aBehrends, Christian$$b12
000285208 7001_ $$00000-0001-5471-6141$$aSambandan, Sivakumar$$b13
000285208 7001_ $$0P:(DE-2719)9000040$$aBurbulla, Lena F.$$b14$$eLast author$$udzne
000285208 773__ $$0PERI:(DE-600)2810933-8$$a10.1126/sciadv.adz5645$$gVol. 12, no. 7, p. eadz5645$$n7$$peadz5645$$tScience advances$$v12$$x2375-2548$$y2026
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