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.

Recent Insights into the Interplay of Alpha-Synuclein and Sphingolipid Signaling in Parkinson’s Disease

“…ASN is a small, 140-amino acid protein encoded by the SNCA gene. The physiological function of ASN is still under debate [16]. However, due to its presence in synapses, ASN is suggested to be connected with synaptic vesicle regulation and neurotransmission [17,18].…”

“…Disorders evoked by ASN pathology so-called synucleinopathies are characterized by cytoplasmic ASN inclusions occurring predominantly in neurons, but also in glial cells. Intraneuronal LBs are a feature of LBDs, which, aside from PD, include dementia with LBs (DLB), PD dementia (PDD), and pure autonomic failure (PAF) [16]. Furthermore, glial cytoplasmic inclusions composed mainly from ASN (Papp-Lantos bodies) play a significant role in multiple system atrophy (MSA) [38].…”

Is Multiple System Atrophy a Prion-like Disorder?

“…The term “propagon” has also been suggested to denominate these proteins that act like prions [ 96 ]. Both evidence of self-templating propagation in cellular cultures, animal models, and in humans are required to define MSA as a prion disease [ 97 ].…”

“…The aggregation of these fibrils and subsequent inclusion formations are suggested to interfere with vesicular trafficking and organelle functions in neurons [ 131 ]. However, the applicability of the prion hypothesis in α-synucleinopathies remains controversial [ 45 , 97 ]. Although some research groups showed the “infectious” activity of LB extracts from PD brains in mice and also in monkeys [ 128 ], demonstrating the prion propensities of αSyn assemblies [ 44 ], so far there is no evidence of pathologic αSyn aggregate transmission between individuals leading to the prion-like definition to make a distinction between this protein and actively infectious prions [ 132 ].…”

Role of Mitochondrial Heat-shock Proteins and Immunophilins in Neuro Degenerative Diseases

“…All these observations highlight the critical role of CHIP and HSPs in Alzheimer's disease, Parkinson's disease, Lewy's Body Disease, prion or huntingtin pathologies. Table 2 summarizes the properties of all HSPs, immunophilins, and other molecular chaperones discussed here that are involved in the biology of aggregated proteins responsible for neurodegenerative diseases [107,135,195,[200][201][202]. [189,191,193,196] PTPA Protects against β-amyloid toxicity Nucleus, cytoplasm AD [131,132] (…”