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000280947 245__ $$aAlpha-synuclein in Parkinson's disease: the debate that must go on.
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000280947 520__ $$aI 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!
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