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@ARTICLE{FloresLen:281351,
      author       = {Flores-León, Manuel and Outeiro, Tiago F},
      title        = {{E}xpanding our understanding of synucleinopathies:
                      proteinopathy, proteinopenia, and lipidopathy.},
      journal      = {The FEBS journal},
      volume       = {292},
      number       = {18},
      issn         = {0014-2956},
      address      = {Oxford [u.a.]},
      publisher    = {Wiley-Blackwell},
      reportid     = {DZNE-2025-01098},
      pages        = {4774 - 4788},
      year         = {2025},
      abstract     = {A possible consequence of the process of protein
                      aggregation in neurodegenerative diseases is the depletion
                      of soluble protein species (proteinopenia), which may, at
                      least in some cases, reduce protein function/activity. This
                      concept, which is often overlooked, may play a role in
                      synucleinopathies such as Parkinson's disease (PD), and
                      dementia with Lewy bodies (DLB), where the protein
                      α-synuclein (aSyn) is known to accumulate in insoluble
                      inclusions. aSyn is at the crossroads between cellular
                      proteostasis and lipidostasis networks and, therefore, we
                      must be aware of the complexity we face when we try to
                      understand the molecular basis of synucleinopathies.
                      Importantly, aSyn and β-glucocerebrosidase (GCase), a
                      sphingolipid hydrolase also strongly implicated in PD and
                      DLB, are connected to lipid biology and to protein quality
                      control function. Thus, changes in the normal relationship
                      between these two proteins may shift the balance in the cell
                      and lead to proteinopathy and/or proteinopenia, while also
                      affecting lipidostasis of cells in the brain. Thus,
                      pathological mechanisms that are a consequence of (a)
                      loss-of-function, (b) gain-of-toxic function, and (c)
                      alterations in lipidostasis need to be carefully analyzed
                      and integrated in our study of the molecular underpinnings
                      of neurodegenerative mechanisms. Here, we highlight
                      implications of the depletion of the soluble form of aSyn,
                      and of GCase, and discuss how state-of-the-art 'omics
                      technologies' could be deployed to assist in the clinical
                      assessment of synucleinopathies.},
      subtyp        = {Review Article},
      keywords     = {Humans / alpha-Synuclein: metabolism / alpha-Synuclein:
                      genetics / Synucleinopathies: metabolism /
                      Synucleinopathies: pathology / Synucleinopathies: genetics /
                      Parkinson Disease: metabolism / Parkinson Disease: pathology
                      / Parkinson Disease: genetics / Glucosylceramidase: genetics
                      / Glucosylceramidase: metabolism / Lipid Metabolism /
                      Animals / Proteostasis: genetics / Lewy Body Disease:
                      metabolism / Lewy Body Disease: pathology / Lewy Body
                      Disease: genetics / Parkinson's disease (Other) /
                      alpha‐synuclein (Other) / lipids (Other) / protein
                      aggregation (Other) / synucleinopathy (Other) /
                      transcription (Other) / alpha-Synuclein (NLM Chemicals) /
                      Glucosylceramidase (NLM Chemicals)},
      cin          = {AG Fischer},
      ddc          = {610},
      cid          = {I:(DE-2719)1410002},
      pnm          = {352 - Disease Mechanisms (POF4-352)},
      pid          = {G:(DE-HGF)POF4-352},
      typ          = {PUB:(DE-HGF)16},
      pubmed       = {pmid:39996490},
      pmc          = {pmc:PMC12443472},
      doi          = {10.1111/febs.70011},
      url          = {https://pub.dzne.de/record/281351},
}