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@ARTICLE{Heger:285208,
      author       = {Heger, Leonie and Gubinelli, Francesco and Huber, Andreas J
                      and Cardona-Alberich, Aida and Rovere, Matteo and Matti, Ulf
                      and Müller, Stephan A and Nagaraja, Sankarshana and
                      Jaschkowitz, Lena and Schifferer, Martina and Wurst,
                      Wolfgang and Lichtenthaler, Stefan F and Behrends, Christian
                      and Sambandan, Sivakumar and Burbulla, Lena F.},
      title        = {{VMAT}2 dysfunction impairs vesicular dopamine uptake,
                      driving its oxidation and α-synuclein pathology in
                      {DJ}-1-linked {P}arkinson's neurons.},
      journal      = {Science advances},
      volume       = {12},
      number       = {7},
      issn         = {2375-2548},
      address      = {Washington, DC [u.a.]},
      publisher    = {Assoc.},
      reportid     = {DZNE-2026-00187},
      pages        = {eadz5645},
      year         = {2026},
      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.},
      keywords     = {Vesicular Monoamine Transport Proteins: metabolism /
                      Vesicular Monoamine Transport Proteins: genetics / Dopamine:
                      metabolism / Parkinson Disease: metabolism / Parkinson
                      Disease: pathology / Parkinson Disease: genetics / Protein
                      Deglycase DJ-1: genetics / Protein Deglycase DJ-1:
                      metabolism / Humans / Dopaminergic Neurons: metabolism /
                      Dopaminergic Neurons: pathology / alpha-Synuclein:
                      metabolism / alpha-Synuclein: genetics / Oxidation-Reduction
                      / Animals / Synaptic Vesicles: metabolism / Mice / Adenosine
                      Triphosphate: metabolism / Induced Pluripotent Stem Cells:
                      metabolism / Mesencephalon: metabolism / Vesicular Monoamine
                      Transport Proteins (NLM Chemicals) / Dopamine (NLM
                      Chemicals) / Protein Deglycase DJ-1 (NLM Chemicals) /
                      alpha-Synuclein (NLM Chemicals) / SLC18A2 protein, human
                      (NLM Chemicals) / Adenosine Triphosphate (NLM Chemicals) /
                      PARK7 protein, human (NLM Chemicals)},
      cin          = {AG Burbulla / AG Lichtenthaler / AG Misgeld / AG Wurst},
      ddc          = {500},
      cid          = {I:(DE-2719)5000074 / I:(DE-2719)1110006 /
                      I:(DE-2719)1110000-4 / I:(DE-2719)1140001},
      pnm          = {352 - Disease Mechanisms (POF4-352) / 351 - Brain Function
                      (POF4-351)},
      pid          = {G:(DE-HGF)POF4-352 / G:(DE-HGF)POF4-351},
      typ          = {PUB:(DE-HGF)16},
      pubmed       = {pmid:41671379},
      pmc          = {pmc:PMC12893317},
      doi          = {10.1126/sciadv.adz5645},
      url          = {https://pub.dzne.de/record/285208},
}