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@ARTICLE{Hfs:281362,
      author       = {Höfs, Lennart and Geißler-Lösch, David and Falkenburger,
                      Björn H},
      title        = {{PLEKHM}1 {O}verexpression {I}mpairs {A}utophagy and
                      {E}xacerbates {N}eurodegeneration in r{AAV}-α-{S}ynuclein
                      {M}ice.},
      journal      = {Cells},
      volume       = {14},
      number       = {17},
      issn         = {2073-4409},
      address      = {Basel},
      publisher    = {MDPI},
      reportid     = {DZNE-2025-01109},
      pages        = {1340},
      year         = {2025},
      abstract     = {The aggregation of α-synuclein (αSyn) is a central
                      feature of Parkinson's disease (PD) and other
                      synucleinopathies. The efficient clearance of αSyn depends
                      largely on the autophagy-lysosomal pathway. Emerging genetic
                      evidence highlights the role of pleckstrin homology and RUN
                      domain-containing M1 protein (PLEKHM1), a critical regulator
                      of autophagosome-lysosome fusion, in the pathogenesis of
                      multiple neurodegenerative diseases. This study investigates
                      the possible effects of increased PLEKHM1 expression on
                      αSyn pathology and neurodegeneration in mice. We utilized a
                      mouse model of PD that is based on A53T-αSyn
                      overexpression, achieved by the stereotactic injection of
                      recombinant adeno-associated viral vectors (rAAV) into the
                      substantia nigra. Additionally, this study explores the
                      effect of PLEKHM1 overexpression on the autophagy-lysosomal
                      pathway under physiological conditions, using transgenic
                      autophagy reporter mice. PLEKHM1 overexpression facilitated
                      the αSyn-induced degeneration of dopaminergic somata in the
                      substantia nigra and degeneration of dopaminergic axon
                      terminals in the striatum. In concert with αSyn expression,
                      PLEKHM1 also potentiated microglial activation. The extent
                      of αSyn pathology, as reported by staining for
                      phosphorylated αSyn, was not affected by PLEKHM1. Using
                      RFP-EGFP-LC3 autophagy reporter mice, rAAV-mediated PLEKHM1
                      overexpression reduced lysosomal and autolysosomal area,
                      increased LAMP1-LC3 colocalization, and decreased the
                      autolysosome-to-autophagosome ratio. Concurrently, PLEKHM1
                      overexpression in both genotypes caused p62 accumulation,
                      accompanied by reduced overlap with lysosomal and
                      autophagosomal markers but increased colocalization with
                      autolysosomal markers, indicating impaired cargo degradation
                      during late-stage autophagy. Taken together, elevated
                      PLEKHM1 levels exacerbate neurodegeneration in
                      αSyn-overexpressing mice, possibly by impairing autophagic
                      flux. Now, with in vivo evidence complementing genetic data,
                      alterations in PLEKHM1 expression appear to compromise
                      autophagy, potentially enhancing neuronal vulnerability to
                      secondary insults like αSyn pathology.},
      keywords     = {Animals / Autophagy: genetics / alpha-Synuclein: metabolism
                      / alpha-Synuclein: genetics / Dependovirus: genetics /
                      Dependovirus: metabolism / Mice / Lysosomes: metabolism /
                      Disease Models, Animal / Mice, Transgenic / Substantia
                      Nigra: metabolism / Substantia Nigra: pathology / Parkinson
                      Disease: pathology / Parkinson Disease: metabolism /
                      Parkinson Disease: genetics / Mice, Inbred C57BL /
                      Dopaminergic Neurons: metabolism / Dopaminergic Neurons:
                      pathology / Male / RFP-EGFP-LC3 mice (Other) /
                      alpha-synuclein (Other) / autophagic flux (Other) /
                      autophagy (Other) / lysosomes (Other) / mouse model (Other)
                      / alpha-Synuclein (NLM Chemicals)},
      cin          = {AG Falkenburger},
      ddc          = {570},
      cid          = {I:(DE-2719)1710012},
      pnm          = {353 - Clinical and Health Care Research (POF4-353)},
      pid          = {G:(DE-HGF)POF4-353},
      typ          = {PUB:(DE-HGF)16},
      pubmed       = {pmid:40940751},
      pmc          = {pmc:PMC12427628},
      doi          = {10.3390/cells14171340},
      url          = {https://pub.dzne.de/record/281362},
}