Abstract
Since its discovery 30 years ago, α-synuclein (α-syn) has been one of the most studied proteins in the field of neuroscience. Dozens of groups worldwide have tried to reveal not only its role in the CNS but also in other organs. α-syn has been linked to several processes essential in brain homeostasis such as neurotransmitter release, synaptic function, and plasticity. However, despite the efforts made in this direction, the main function of α-syn is still unknown. Moreover, α-syn became a protein of interest for neurologists and neuroscientists when mutations in its gene were found associated with Parkinson’s disease (PD) and even more when α-syn protein deposits were observed in the brain of PD, dementia with Lewy bodies (DLB), and multiple system atrophy (MSA) patients. At present, the abnormal accumulation of α-syn constitutes one of the pathological hallmarks of these disorders, also referred to as α-synucleinopathies, and it is used for post-mortem diagnostic criteria. Whether α-syn aggregation is cause or consequence of the pathogenic events underlying α-synucleinopathies remains unclear and under discussion. Recently, different in vitro and in vivo studies have shown the ability of pathogenic α-syn to spread between cells, not only within the CNS but also from peripheral locations such as the gut, salivary glands, and through the olfactory network into the CNS, inducing abnormal misfolding of endogenous α-syn and leading to neurodegeneration and motor and cognitive impairment in animal models. Thus, it has been suggested that α-syn should be considered a prion protein. Here we present an update of what we know about α-syn function, aggregation and spreading, and its role in neurodegeneration. We also discuss the rationale and findings supporting the hypothetical prion nature of α-syn, its weaknesses, and future perspectives for research and the development of disease-modifying therapies.
Highlights
Since its discovery 30 years ago, α-synuclein (α-syn) has been one of the most studied proteins in the field of neuroscience
Α-syn became a protein of interest for neurologists and neuroscientists when mutations in its gene were found associated with Parkinson’s disease (PD) and even more when α-syn protein deposits were observed in the brain of PD, dementia with Lewy bodies (DLB), and multiple system atrophy (MSA) patients
We recently showed that targeting α-syn oligomerization in an animal model for MSA led to a decrease of α-syn aggregates which significantly correlated with neuroprotection and a reduction in microglial activation (HerasGarvin et al, 2019)
Summary
Α-synuclein (α-syn) is one of the most abundant proteins in the nervous system, encoded by the SNCA gene. The fact that α-syn aggregates were found in human brain regions affected by the disease and that some studies, like the one conducted by Braak et al (2004) showed the presence of inclusions in peripheral organs and described an association between disease stage and Lewy pathology, led the authors to propose that αsynucleinopathies could initiate in the gut or the olfactory bulb and slowly spread to the CNS (Beach et al, 2009) This evidence and the data demonstrating the ability of α-syn to propagate from the gut and other peripheral organs in animal models (Kim S. et al, 2019; Lohmann et al, 2019) as well as the finding of LBs in grafted dopaminergic neurons in PD patients (Kordower et al, 2008; Li et al, 2008) supported the prion nature of α-syn. The distinct efficacies observed between preclinical studies, based on in vitro and in vivo models, and the data from human studies could be explained by the neurobiological differences among species, but may be a consequence of current limitations to recruit patients at early stages of the disease, when significant neurodegeneration and motor symptoms are not yet present, to misdiagnosis and to the absence of specific biomarkers for α-syn
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