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@ARTICLE{Pollmanns:164948,
      author       = {Pollmanns, Maike R and Beer, Judith and Rosignol, Ines and
                      Rodriguez-Muela, Natalia and Falkenburger, Björn H and
                      Dinter, Elisabeth},
      title        = {{A}ctivated {E}ndolysosomal {C}ation {C}hannel {TRPML}1
                      {F}acilitates {M}aturation of α-{S}ynuclein-{C}ontaining
                      {A}utophagosomes.},
      journal      = {Frontiers in cellular neuroscience},
      volume       = {16},
      issn         = {1662-5102},
      address      = {Lausanne},
      publisher    = {Frontiers Research Foundation},
      reportid     = {DZNE-2022-01352},
      pages        = {861202},
      year         = {2022},
      abstract     = {Background: Protein aggregates are degraded via the
                      autophagy-lysosome pathway and alterations in the lysosomal
                      system leading to the accumulation of pathogenic proteins,
                      including aggregates of α-synuclein in Parkinson's disease
                      (PD). The importance of the endolysosomal transient receptor
                      potential cation channel, mucolipin subfamily 1 (TRPML1) for
                      the lysosomal function is highlighted by the fact that
                      TRPML1 mutations cause the lysosomal storage disease
                      mucolipidosis type IV. In this study, we investigated the
                      mechanism by which activation of TRPML1 affects the
                      degradation of α-synuclein. Methods: As a model of
                      α-synuclein pathology, we expressed the pathogenic
                      A53Tα-synuclein mutant in HEK293T cells. These cells were
                      treated with the synthetic TRPML1 agonist ML-SA1. The amount
                      of α-synuclein protein was determined by immunoblots. The
                      abundance of aggregates and autolysosomal vesicles was
                      determined by fluorescence microscopy and
                      immunocytochemistry. Findings were confirmed by life-cell
                      imaging and by application of ML-SA1 and the TRPML1
                      antagonist ML-SI3 to human dopaminergic neurons and human
                      stem cell-derived neurons. Results: ML-SA1 reduced the
                      percentage of HEK293T cells with α-synuclein aggregates and
                      the amount of α-synuclein protein. The effect of ML-SA1 was
                      blocked by pharmacological and genetic inhibition of
                      autophagy. Consistent with TRPML function, it required the
                      membrane lipid PI(3,5)P2, and cytosolic calcium. ML-SA1
                      shifted the composition of autophagosomes towards a higher
                      fraction of mature autolysosomes, also in presence of
                      α-synuclein. In neurons, inhibition of TRPML1 by its
                      antagonist ML-SI3 blocked autophagosomal clearance, whereas
                      the agonist ML-SA1 shifted the composition of a-synuclein
                      particles towards a higher fraction of acidified particles.
                      ML-SA1 was able to override the effect of Bafilomycin A1,
                      which blocks the fusion of the autophagosome and lysosome
                      and its acidification. Conclusion: These findings suggest,
                      that activating TRPML1 with ML-SA1 facilitates clearance of
                      α-synuclein aggregates primarily by affecting the late
                      steps of the autophagy, i.e., by promoting autophagosome
                      maturation. In agreement with recent work by others, our
                      findings indicate that TRPML1 might constitute a plausible
                      therapeutic target for PD, that warrants further validation
                      in rodent models of α-synuclein pathology.},
      keywords     = {ML-SA1 (Other) / Parkinson’s disease (Other) / TRPML1
                      (Other) / acidification (Other) / autolysosome maturation
                      (Other) / autophagy (Other) / mucolipin-1 (Other) /
                      synuclein (Other)},
      cin          = {AG Falkenburger / AG Rodriguez-Muela},
      ddc          = {610},
      cid          = {I:(DE-2719)1710012 / I:(DE-2719)1713001},
      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:35875350},
      pmc          = {pmc:PMC9296810},
      doi          = {10.3389/fncel.2022.861202},
      url          = {https://pub.dzne.de/record/164948},
}