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@ARTICLE{Knab:282566,
      author       = {Knab, Felix and Lee, Jun-Hoe and Nirujogi, Raja and Menden,
                      Kevin and Braunger, Luca and Logarnudi, Lambrianna and
                      Riebenbauer, Benjamin and Isik, Fatma Busra and Rajkumar,
                      Anto Praveen and Czemmel, Stefan and Fitzgerald, Julia and
                      Gasser, Thomas and Gloeckner, Christian Johannes},
      title        = {{C}ellular and {E}xtracellular {M}icro{RNA} {D}ysregulation
                      in {LRRK}2-{L}inked {P}arkinson's {D}isease.},
      journal      = {Molecular neurobiology},
      volume       = {63},
      number       = {1},
      issn         = {0893-7648},
      address      = {Totowa, NJ},
      publisher    = {Humana Press},
      reportid     = {DZNE-2025-01329},
      pages        = {189},
      year         = {2025},
      abstract     = {Cell-free microRNAs in body fluids have emerged as
                      promising biomarker candidates in neurodegenerative
                      diseases. While several studies have identified dysregulated
                      miRNAs in sporadic Parkinson's disease, it remains unclear
                      whether distinguishable alterations of cell-free miRNAs
                      occur in genetic forms of the disease, such as those
                      associated with the LRRK2 G2019S mutation. In this
                      proof-of-concept study, we used a human induced pluripotent
                      stem cell-derived dopaminergic neuron model to investigate
                      whether the LRRK2 G2019S mutation induces detectable changes
                      in the intra- and extracellular miRNAome, and whether miRNA
                      signatures identified in vitro can be validated in
                      patient-derived cerebrospinal fluid. We differentiated
                      dopaminergic neurons from induced pluripotent stem cells
                      carrying the LRRK2 G2019S mutation and an isogenic
                      gene-corrected control. Extracellular vesicles were isolated
                      from the culture medium and used as a source of cell-free
                      miRNA. Next, small RNA libraries were generated and
                      analyzed. Differentially expressed microRNAs were validated
                      in an independent batch using RT-qPCR. We further quantified
                      candidate microRNAs in cerebrospinal fluid samples from five
                      LRRK2 G2019S patients and matching healthy controls. The
                      patient cohort included the fibroblast donor from whom the
                      stem cells were originally derived. We successfully isolated
                      extracellular vesicles from induced pluripotent stem
                      cell-derived human dopaminergic neurons. We identified a
                      distinct set of differentially expressed miRNAs in cellular
                      and cell-free RNA, among which let-7g-5p and miR-21-5p were
                      consistently upregulated and validated across independent
                      replicates. These alterations were reflected in the
                      cerebrospinal fluid of the original donor and partially
                      reproduced in additional LRRK2 patients, supporting the
                      concept of patient-specific signatures. A strong correlation
                      between intra- and extracellular miRNA expression was
                      observed. Our findings demonstrate that induced pluripotent
                      stem cell-derived dopaminergic neurons can serve as a model
                      to identify individualized, cell-free microRNA signatures
                      associated with the LRRK2 G2019S mutation. The dysregulated
                      miRNAs detected in vitro were mirrored in patient
                      cerebrospinal fluid, supporting their potential as
                      accessible molecular readouts. These results lay the
                      groundwork for personalized biomarker strategies in genetic
                      forms of Parkinson's disease and warrant further validation
                      in larger patient cohorts.},
      keywords     = {Humans / Leucine-Rich Repeat Serine-Threonine Protein
                      Kinase-2: genetics / Leucine-Rich Repeat Serine-Threonine
                      Protein Kinase-2: metabolism / MicroRNAs: genetics /
                      MicroRNAs: metabolism / MicroRNAs: cerebrospinal fluid /
                      Parkinson Disease: genetics / Parkinson Disease:
                      cerebrospinal fluid / Induced Pluripotent Stem Cells:
                      metabolism / Dopaminergic Neurons: metabolism / Dopaminergic
                      Neurons: pathology / Extracellular Vesicles: metabolism /
                      Mutation: genetics / Cell Differentiation / Middle Aged /
                      Male / Female / Biomarker (Other) / IPSCs (Other) / LRRK2
                      (Other) / Micro-RNA (Other) / Parkinson’s disease (Other)
                      / Leucine-Rich Repeat Serine-Threonine Protein Kinase-2 (NLM
                      Chemicals) / MicroRNAs (NLM Chemicals) / LRRK2 protein,
                      human (NLM Chemicals)},
      cin          = {AG Gasser / AG Gloeckner},
      ddc          = {570},
      cid          = {I:(DE-2719)1210000 / I:(DE-2719)1210007},
      pnm          = {353 - Clinical and Health Care Research (POF4-353) / 352 -
                      Disease Mechanisms (POF4-352)},
      pid          = {G:(DE-HGF)POF4-353 / G:(DE-HGF)POF4-352},
      typ          = {PUB:(DE-HGF)16},
      pubmed       = {pmid:41298996},
      pmc          = {pmc:PMC12657546},
      doi          = {10.1007/s12035-025-05379-2},
      url          = {https://pub.dzne.de/record/282566},
}