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@ARTICLE{Redl:281869,
      author       = {Redl, Stefan and Zweydorf, Felix and Gloeckner, Christian J
                      and Posadas, Inmaculada and Ceña, Valentín and Hess,
                      Michael W and Piccoli, Giovanni and Pérez-Carrión, María
                      Dolores},
      title        = {{T}he {E}193{K} {LRRK}2 mutation interferes with the
                      autophagosome processing through the impairment of the
                      {LRRK}2-{D}ynein-1 complex.},
      journal      = {Scientific reports},
      volume       = {15},
      number       = {1},
      issn         = {2045-2322},
      address      = {[London]},
      publisher    = {Springer Nature},
      reportid     = {DZNE-2025-01240},
      pages        = {39117},
      year         = {2025},
      abstract     = {Parkinson's disease (PD) is a neurodegenerative pathology
                      characterized by movement-associated symptoms due to the
                      selective loss of dopaminergic neurons in the substantia
                      nigra pars compacta. Autophagy is an essential mechanism
                      that restores homeostasis and promotes cell survival.
                      Mutations in the Leucine-Rich Repeat Kinase 2 (LRRK2) gene
                      are among the most common in the familial cases. The LRRK2
                      E193K mutation falls in the Armadillo (ARM) domain and
                      modifies LRRK2 interactome. The role of LRRK2 in autophagy
                      has been widely explored, but the impact of E193K mutation
                      on autophagy remains unknown. We found that the E193K
                      variant increases autophagy in primary fibroblasts obtained
                      from an E193K carrier. By cryo-based electron microscopy we
                      observed that E193K fibroblasts present a higher amount of
                      phagophores/autophagosomes. We showed that LRRK2 binds to
                      the Dynein-1 complex, an essential regulator of retrograde
                      transport of autophagosomes. Noteworthy, the E193K mutation
                      jeopardizes this interaction and increases the cellular
                      sensitivity to 1-methyl-4-phenylpyridinium (MPP+) toxin in
                      fibroblasts as well as in a heterologous cell model. Our
                      study reveals that the LRRK2 E193K variant influences the
                      autophagic regulation and suggests that the dysregulation of
                      the LRRK2-Dynein-1 complex causes autophagic defects and,
                      eventually, cell death.},
      keywords     = {Leucine-Rich Repeat Serine-Threonine Protein Kinase-2:
                      genetics / Leucine-Rich Repeat Serine-Threonine Protein
                      Kinase-2: metabolism / Humans / Autophagosomes: metabolism /
                      Fibroblasts: metabolism / Autophagy: genetics / Mutation /
                      Parkinson Disease: genetics / Parkinson Disease: metabolism
                      / Parkinson Disease: pathology / Dyneins: metabolism /
                      Dyneins: genetics / Protein Binding / Autophagy (Other) /
                      Dynein-1 complex (Other) / LRRK2 protein (Other) / Organelle
                      morphometry (Other) / Parkinson´s disease (Other) /
                      Ultrastructure (Other) / Leucine-Rich Repeat
                      Serine-Threonine Protein Kinase-2 (NLM Chemicals) / LRRK2
                      protein, human (NLM Chemicals) / Dyneins (NLM Chemicals)},
      cin          = {AG Gloeckner},
      ddc          = {600},
      cid          = {I:(DE-2719)1210007},
      pnm          = {352 - Disease Mechanisms (POF4-352)},
      pid          = {G:(DE-HGF)POF4-352},
      typ          = {PUB:(DE-HGF)16},
      pubmed       = {pmid:41203815},
      pmc          = {pmc:PMC12594833},
      doi          = {10.1038/s41598-025-26716-4},
      url          = {https://pub.dzne.de/record/281869},
}