Home > In process > VMAT2 dysfunction impairs vesicular dopamine uptake, driving its oxidation and α-synuclein pathology in DJ-1-linked Parkinson's neurons. > print

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100 1 _ |a Heger, Leonie
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245 _ _ |a VMAT2 dysfunction impairs vesicular dopamine uptake, driving its oxidation and α-synuclein pathology in DJ-1-linked Parkinson's neurons.
260 _ _ |a Washington, DC [u.a.]
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520 _ _ |a 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.
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650 _ 7 |a Vesicular Monoamine Transport Proteins
|2 NLM Chemicals
650 _ 7 |a Dopamine
|0 VTD58H1Z2X
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650 _ 7 |a Protein Deglycase DJ-1
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650 _ 7 |a alpha-Synuclein
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650 _ 7 |a SLC18A2 protein, human
|2 NLM Chemicals
650 _ 7 |a Adenosine Triphosphate
|0 8L70Q75FXE
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650 _ 7 |a PARK7 protein, human
|0 EC 3.1.2.-
|2 NLM Chemicals
650 _ 2 |a Vesicular Monoamine Transport Proteins: metabolism
|2 MeSH
650 _ 2 |a Vesicular Monoamine Transport Proteins: genetics
|2 MeSH
650 _ 2 |a Dopamine: metabolism
|2 MeSH
650 _ 2 |a Parkinson Disease: metabolism
|2 MeSH
650 _ 2 |a Parkinson Disease: pathology
|2 MeSH
650 _ 2 |a Parkinson Disease: genetics
|2 MeSH
650 _ 2 |a Protein Deglycase DJ-1: genetics
|2 MeSH
650 _ 2 |a Protein Deglycase DJ-1: metabolism
|2 MeSH
650 _ 2 |a Humans
|2 MeSH
650 _ 2 |a Dopaminergic Neurons: metabolism
|2 MeSH
650 _ 2 |a Dopaminergic Neurons: pathology
|2 MeSH
650 _ 2 |a alpha-Synuclein: metabolism
|2 MeSH
650 _ 2 |a alpha-Synuclein: genetics
|2 MeSH
650 _ 2 |a Oxidation-Reduction
|2 MeSH
650 _ 2 |a Animals
|2 MeSH
650 _ 2 |a Synaptic Vesicles: metabolism
|2 MeSH
650 _ 2 |a Mice
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650 _ 2 |a Adenosine Triphosphate: metabolism
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650 _ 2 |a Induced Pluripotent Stem Cells: metabolism
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650 _ 2 |a Mesencephalon: metabolism
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700 1 _ |a Gubinelli, Francesco
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700 1 _ |a Huber, Andreas J
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700 1 _ |a Cardona-Alberich, Aida
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700 1 _ |a Rovere, Matteo
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700 1 _ |a Lichtenthaler, Stefan F
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700 1 _ |a Sambandan, Sivakumar
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700 1 _ |a Burbulla, Lena F.
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