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@ARTICLE{Knab:274040,
      author       = {Knab, Felix and Guaitoli, Giambattista and Jarboui, Mohamed
                      Ali and von Zweydorf, Felix and Isik, Fatma Busra and Klose,
                      Franziska and Rajkumar, Anto Praveen and Gasser, Thomas and
                      Gloeckner, Christian Johannes},
      title        = {{T}he cellular and extracellular proteomic signature of
                      human dopaminergic neurons carrying the {LRRK}2 {G}2019{S}
                      mutation.},
      journal      = {Frontiers in neuroscience},
      volume       = {18},
      issn         = {1662-4548},
      address      = {Lausanne},
      publisher    = {Frontiers Research Foundation},
      reportid     = {DZNE-2025-00021},
      pages        = {1502246},
      year         = {2024},
      abstract     = {Extracellular vesicles are easily accessible in various
                      biofluids and allow the assessment of disease-related
                      changes in the proteome. This has made them a promising
                      target for biomarker studies, especially in the field of
                      neurodegeneration where access to diseased tissue is very
                      limited. Genetic variants in the LRRK2 gene have been linked
                      to both familial and sporadic forms of Parkinson's disease.
                      With LRRK2 inhibitors entering clinical trials, there is an
                      unmet need for biomarkers that reflect LRRK2-specific
                      pathology and target engagement.In this study, we used
                      induced pluripotent stem cells derived from a patient with
                      Parkinson's disease carrying the LRRK2 G2019S mutation and
                      an isogenic gene-corrected control to generate human
                      dopaminergic neurons. We isolated extracellular vesicles and
                      neuronal cell lysates and characterized their proteomic
                      signature using data-independent acquisition proteomics.
                      Then, we performed differential expression analysis to
                      identify dysregulated proteins in the mutated line. We used
                      Metascape and gene ontology enrichment analysis on the
                      dysregulated proteomes to identify changes in associated
                      functional networks.We identified 595 significantly
                      differentially regulated proteins in extracellular vesicles
                      and 3,205 in cell lysates. We visualized functionally
                      relevant protein-protein interaction networks and identified
                      key regulators within the dysregulated proteomes. Using gene
                      ontology, we found a close association with biological
                      processes relevant to neurodegeneration and Parkinson's
                      disease. Finally, we focused on proteins that were
                      dysregulated in both the extracellular and cellular
                      proteomes. We provide a list of ten biomarker candidates
                      that are functionally relevant to neurodegeneration and
                      linked to LRRK2-associated pathology, for example, the sonic
                      hedgehog signaling molecule, a protein that has tightly been
                      linked to LRRK2-related disruption of cilia function.In
                      conclusion, we characterized the cellular and extracellular
                      proteome of dopaminergic neurons carrying the LRRK2 G2019S
                      mutation and proposed an experimentally based list of
                      biomarker candidates for future studies.},
      keywords     = {LRRK2 (Other) / Parkinson’s disease (Other) / biomarker
                      (Other) / extracellular vesicle (Other) / induced
                      pluripotent stem cell (Other)},
      cin          = {AG Gloeckner / AG Gasser},
      ddc          = {610},
      cid          = {I:(DE-2719)1210007 / I:(DE-2719)1210000},
      pnm          = {352 - Disease Mechanisms (POF4-352) / 353 - Clinical and
                      Health Care Research (POF4-353)},
      pid          = {G:(DE-HGF)POF4-352 / G:(DE-HGF)POF4-353},
      typ          = {PUB:(DE-HGF)16},
      pubmed       = {pmid:39726830},
      pmc          = {pmc:PMC11669673},
      doi          = {10.3389/fnins.2024.1502246},
      url          = {https://pub.dzne.de/record/274040},
}