From Synaptic Protein to Prion: The Long and Controversial Journey of α-Synuclein

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.

Keywords: Parkinson’s disease; neurodegeneration; prion; α-synuclein; α-synucleinopathies.

Figure 1

Physiological roles of α-synuclein (α-syn). Schematic overview including some of the cellular processes linked to α-syn in physiological conditions.

Figure 2

Pathological roles of α-syn. Schematic overview including some of the cellular processes (left) and histopathological events (right) associated with the presence of pathogenic α-syn species.

Figure 3

α-synuclein aggregation process. Schematic overview of the hypothetical aggregation process of monomeric α-syn and the different events that can induce its misfolding and promote aggregation.

Figure 4

Prion protein vs. α-synuclein: current knowledge. Both proteins can undergo misfolding (1) which leads to the formation of different pathogenic strains (2). The pathogenic forms of both proteins can be transferred cell-to-cell (3) and spread from the periphery into the CNS in vivo (4). However, based on post-mortem data from α-synucleinopathy patients and in contrast to the prion protein, it is not clear how and where does α-synuclein pathology start and if the spreading observed in in vivo studies really happens in humans (4). Finally, unlike prion protein, no evidence of intraspecies or interpecies transmission of α-syn has ever been reported (5).