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@ARTICLE{Schildknecht:136890,
      author       = {Schildknecht, Stefan and Gerding, Hanne R and Karreman,
                      Christiaan and Drescher, Malte and Lashuel, Hilal A and
                      Outeiro, Tiago F and Di Monte, Donato A and Leist, Marcel},
      title        = {{O}xidative and nitrative alpha-synuclein modifications and
                      proteostatic stress: implications for disease mechanisms and
                      interventions in synucleinopathies.},
      journal      = {Journal of neurochemistry},
      volume       = {125},
      number       = {4},
      issn         = {0022-3042},
      address      = {Oxford},
      publisher    = {Wiley-Blackwell},
      reportid     = {DZNE-2020-03212},
      pages        = {491-511},
      year         = {2013},
      abstract     = {Alpha-synuclein (ASYN) is a major constituent of the
                      typical protein aggregates observed in several
                      neurodegenerative diseases that are collectively referred to
                      as synucleinopathies. A causal involvement of ASYN in the
                      initiation and progression of neurological diseases is
                      suggested by observations indicating that single-point
                      (e.g., A30P, A53T) or multiplication mutations of the gene
                      encoding for ASYN cause early onset forms of Parkinson's
                      disease (PD). The relative regional specificity of ASYN
                      pathology is still a riddle that cannot be simply explained
                      by its expression pattern. Also, transgenic over-expression
                      of ASYN in mice does not recapitulate the typical
                      dopaminergic neuronal death observed in PD. Thus, additional
                      factors must contribute to ASYN-related toxicity. For
                      instance, synucleinopathies are usually associated with
                      inflammation and elevated levels of oxidative stress in
                      affected brain areas. In turn, these conditions favor
                      oxidative modifications of ASYN. Among these modifications,
                      nitration of tyrosine residues, formation of covalent ASYN
                      dimers, as well as methionine sulfoxidations are prominent
                      examples that are observed in post-mortem PD brain sections.
                      Oxidative modifications can affect ASYN aggregation, as well
                      as its binding to biological membranes. This would affect
                      neurotransmitter recycling, mitochondrial function and
                      dynamics (fission/fusion), ASYN's degradation within a cell
                      and, possibly, the transfer of modified ASYN to adjacent
                      cells. Here, we propose a model on how covalent
                      modifications of ASYN link energy stress, altered
                      proteostasis, and oxidative stress, three major pathogenic
                      processes involved in PD progression. Moreover, we
                      hypothesize that ASYN may act physiologically as a
                      catalytically regenerated scavenger of oxidants in healthy
                      cells, thus performing an important protective role prior to
                      the onset of disease or during aging.},
      subtyp        = {Review Article},
      keywords     = {Humans / Nerve Degeneration: metabolism / Nerve
                      Degeneration: pathology / Nitric Oxide: metabolism /
                      Oxidative Stress: physiology / Parkinson Disease: metabolism
                      / Parkinson Disease: pathology / Peroxynitrous Acid:
                      metabolism / alpha-Synuclein: metabolism / SNCA protein,
                      human (NLM Chemicals) / alpha-Synuclein (NLM Chemicals) /
                      Peroxynitrous Acid (NLM Chemicals) / Nitric Oxide (NLM
                      Chemicals)},
      cin          = {AG Di Monte},
      ddc          = {610},
      cid          = {I:(DE-2719)1013008},
      pnm          = {342 - Disease Mechanisms and Model Systems (POF3-342)},
      pid          = {G:(DE-HGF)POF3-342},
      typ          = {PUB:(DE-HGF)16},
      pubmed       = {pmid:23452040},
      doi          = {10.1111/jnc.12226},
      url          = {https://pub.dzne.de/record/136890},
}