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@ARTICLE{Brs:165354,
      author       = {Brás, Inês C and Khani, Mohammad H and Vasili, Eftychia
                      and Möbius, Wiebke and Riedel, Dietmar and Parfentev, Iwan
                      and Gerhardt, Ellen and Fahlbusch, Christiane and Urlaub,
                      Henning and Zweckstetter, Markus and Gollisch, Tim and
                      Outeiro, Tiago F},
      title        = {{M}olecular {M}echanisms {M}ediating the {T}ransfer of
                      {D}isease-{A}ssociated {P}roteins and {E}ffects on
                      {N}euronal {A}ctivity.},
      journal      = {Journal of Parkinson's Disease},
      volume       = {12},
      number       = {8},
      issn         = {1877-7171},
      address      = {Amsterdam},
      publisher    = {IOS Press},
      reportid     = {DZNE-2022-01631},
      pages        = {2397 - 2422},
      year         = {2022},
      abstract     = {Various cellular pathways have been implicated in the
                      transfer of disease-related proteins between cells,
                      contributing to disease progression and neurodegeneration.
                      However, the overall effects of protein transfer are still
                      unclear.Here, we performed a systematic comparison of basic
                      molecular mechanisms involved in the release of
                      alpha-synuclein, Tau, and huntingtin, and evaluated
                      functional effects upon internalization by receiving
                      cells.Evaluation of protein release to the extracellular
                      space in a free form and in extracellular vesicles using an
                      optimized ultracentrifugation protocol. The extracellular
                      effects of the proteins and extracellular vesicles in
                      primary neuronal cultures were assessed using multi-channel
                      electrophysiological recordings combined with a customized
                      spike sorting framework.We demonstrate cells differentially
                      release free-forms of each protein to the extracellular
                      space. Importantly, neuronal activity is distinctly
                      modulated upon protein internalization in primary cortical
                      cultures. In addition, these disease-related proteins also
                      occur in extracellular vesicles, and are enriched in
                      ectosomes. Internalization of ectosomes and exosomes by
                      primary microglial or astrocytic cells elicits the
                      production of pro-inflammatory cytokines, and modifies
                      spontaneous electrical activity in neurons.Overall, our
                      study demonstrates that released proteins can have
                      detrimental effects for surrounding cells, and suggests
                      protein release pathways may be exploited as therapeutic
                      targets in different neurodegenerative diseases.},
      keywords     = {Humans / Parkinson Disease: metabolism / Neurons:
                      metabolism / Exosomes: metabolism / Protein Transport /
                      Alpha-synuclein (Other) / Tau (Other) / extracellular
                      vesicles (Other) / huntingtin (Other) / neuronal function
                      (Other)},
      cin          = {AG Fischer / AG Zweckstetter},
      ddc          = {610},
      cid          = {I:(DE-2719)1410002 / I:(DE-2719)1410001},
      pnm          = {352 - Disease Mechanisms (POF4-352)},
      pid          = {G:(DE-HGF)POF4-352},
      typ          = {PUB:(DE-HGF)16},
      pubmed       = {pmid:36278361},
      doi          = {10.3233/JPD-223516},
      url          = {https://pub.dzne.de/record/165354},
}