% IMPORTANT: The following is UTF-8 encoded.  This means that in the presence
% of non-ASCII characters, it will not work with BibTeX 0.99 or older.
% Instead, you should use an up-to-date BibTeX implementation like “bibtex8” or
% “biber”.

@ARTICLE{Outeiro:280947,
      author       = {Outeiro, Tiago},
      title        = {{A}lpha-synuclein in {P}arkinson's disease: the debate that
                      must go on.},
      journal      = {Parkinsonism $\&$ related disorders},
      volume       = {136},
      issn         = {1353-8020},
      address      = {Amsterdam [u.a.]},
      publisher    = {Elsevier Science},
      reportid     = {DZNE-2025-01029},
      pages        = {107850},
      year         = {2025},
      abstract     = {I read with great interest and respect, the point of view
                      by Espay and collagues entitled “The α-synuclein seed
                      amplification assay: Interpreting a test of Parkinson's
                      pathology” [1]. I have been working in the field of
                      alpha-synuclein (aSyn) biology and pathobiology for quite
                      some time now, and I am always interested in understanding
                      the ideas circulating in the field. I admire Espay and all
                      the other co-authors for their critical assessment of
                      current short-comings in the field. I admit, I also share
                      the concern that not all our current ideas fit perfectly,
                      and that we must continue our scientific quest for
                      understanding the role of aSyn in Parkinson's disease (PD)
                      and related synucleinopathies. However, we also cannot
                      disregard a wealth of evidence that implicates aSyn as a
                      central player in PD – for the sake of fairness, I
                      highlight the strongest evidence, from genetic studies: (i)
                      several point mutations are linked with familial forms of
                      the disease (for example, see Refs. [2,3]).; multiplications
                      on the SNCA gene are associated with familial forms of PD
                      [4]; several genome-wide association studies have
                      consistently identified the SNCA gene as a risk factor for
                      PD [5].Nevertheless, I agree there are open questions, and
                      that the presence of aSyn in the pathognomonic inclusions
                      found in the brains of patients with synucleinopathies does
                      not prove they are the culprits - after all, Lewy bodies are
                      composed of a couple of hundred proteins, in addition to
                      aSyn. We know well that there are cases of brains displaying
                      Lewy pathology without clinical signs of parkinsonism (cases
                      known as incidental Lewy body disease). We also know there
                      are cases of genetic forms of PD that do not show the
                      typical Lewy pathology. These exceptions should make us
                      cautious, should spark our curiosity, and inspire our
                      research. Importantly, I am among those who believe that, in
                      order to understand the role of aSyn in PD, we need to
                      understand the biological/physiological function it plays in
                      the cell. As a basic scientist, I have seen many examples
                      where knockout studies in rodents have failed to inform
                      about the correct function of a protein [[6], [7], [8]].
                      Likewise, studies involving protein overexpression often
                      fail to inform on real disease mechanisms. Therefore, it is
                      unreasonable to cite such studies to support an argument
                      that, as of yet, we cannot possibly disentangle.I and
                      several other researchers have been raising the idea that PD
                      and related disorders are unlikely to be simply
                      proteinopathies. There may also be a dimension of
                      proteinopenia, a theory that has actually been around for
                      quite some time as loss-of-function, and there may be other
                      dimensions, such as those associated with alterations in
                      lipidostasis [9].The point of view by Espay and colleagues
                      questions the use of the seeding amplification assay (SAA)
                      as a marker of pathology. I follow the argumentation put
                      forward by the authors, but I disagree with the
                      interpretation, which I find skewed – the virtue of the
                      aSyn SAA is not that it is necessarily a marker of pathology
                      and, in its current stage, it is also not a marker of
                      progression. However, it is a sensitive biomarker,
                      separating most PD cases from controls, according to many
                      studies (refs), and it is not meant to inform on disease
                      mechanisms. Using analogies, does measuring glycated
                      hemoglobin inform on molecular mechanisms leading to
                      diabetes? Or does measuring cholesteremia inform on
                      mechanisms leading to stroke? The answer is no to both
                      questions, but I hope we all agree that these measurements
                      inform on risk for developing serious illnesses.Whether
                      protein aggregation is a mechanism of protein precipitation
                      or not is not relevant for this debate. These are
                      technicalities that need to be discussed at length
                      elsewhere, to avoid misconceptions, and to identify possible
                      problems in the underlying theories. But this is much beyond
                      the point, and does not “kill” the aSyn SAA as a tool
                      that performs remarkably well in distinguishing at risk
                      individuals (with RBD) and patients from controls, as
                      demonstrated by a multitude of independent studies.
                      Strinkingly, the real-time quaking-induced conversion
                      (RT–QuIC) assay, developed originally for the prion
                      protein, as a biomarker for prion diseases, is currently
                      approved by the centers for disease control in the USA and
                      in Europe, supporting its widely acknowledged validity as a
                      diagnostic tool.Ongoing efforts for developing aSyn PET
                      tracers will enable us to correlate SAA results with aSyn
                      accumulations, and may shed additional light into the
                      correlation of aSyn accumulation with disease
                      progression.The debate about the biological classification
                      of PD is a separate one, and is just starting. The two
                      systems currently on the table are the first attempts to
                      harness various levels of biological information in order to
                      distinguish patients – something that is essential for
                      improving our chances of success in clinical trials [10,11].
                      Improved versions of these classification systems will
                      emerge, and will require continuous refinement, in order to
                      achieve the goals of enabling disease characterization and
                      informing on precision medicine.In conclusion, we will need
                      the collective work of experts in the field, capable of
                      weighing in arguments in favor and against, in order to make
                      sense of this complex riddle and, hopefully, to devise
                      strategies capable of helping those in need – the patients
                      and their families. Therefore, I could not agree more with
                      Prof. Fernandez: it is not yet time to chose a side! The
                      show must go on!},
      subtyp        = {Letter},
      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:40312239},
      doi          = {10.1016/j.parkreldis.2025.107850},
      url          = {https://pub.dzne.de/record/280947},
}