α-Synuclein in Parkinson’s disease: causal or bystander?

The aggregation of alpha synuclein (a-syn) is a neuropatho-logical feature that defines a spectrum of disorders collectively termed synucleinopathies, and of these, Parkinson's disease (PD) is arguably the best characterized. Aggregated a-syn is the primary component of Lewy bodies, the defining pathological feature of PD, while mutations or multiplications in the a-syn gene result in familial PD. The high correlation between a-syn burden and PD has led to the hypothesis that a-syn aggregation produces toxicity through a gain-of-function mechanism. However, a-syn has been implicated to function in a diverse range of essential cellular processes such as the regulation of neurotransmission and response to cellular stress. As such, an alternative hypothesis with equal explanatory power is that the aggregation of a-syn results in toxicity because of a toxic loss of necessary a-syn function, following sequestration of functional forms a-syn into insoluble protein aggregates. Within this review, we will provide an overview of the literature linking a-syn to PD and the knowledge gained from current a-syn-based animal models of PD. We will then interpret these data from the viewpoint of the a-syn loss-of-function hypothesis and provide a potential mechanistic model by which loss of a-syn function could result in at least some of the neurodegeneration observed in PD. By providing an alternative perspective on the etiopathogenesis of PD and synucleinopathies, this may reveal alternative avenues of research in order to identify potential novel therapeutic targets for disease modifying strategies.

Journal of Parkinson's disease, 2013

The pathogenesis of many neurodegenerative disorders arises in association with the misfolding and accumulation of a wide variety of proteins. Much emphasis has been placed on understanding the nature of these protein accumulations, including their composition, the process by which they are formed and the physiological impact they impose at cellular and, ultimately, organismal levels. Alpha-synuclein (ASYN) is the major component of protein inclusions known as Lewy bodies and Lewy neurites, which are the typical pathological hallmarks in disorders referred to as synucleinopathies. In addition, mutations or multiplications in the gene encoding for ASYN have also been shown to cause familial cases of PD, the most common synucleinopathy. Although the precise function of ASYN remains unclear, it appears to be involved in a vast array of cellular processes. Here, we review, in depth, a spectrum of cellular and molecular mechanisms that have been implicated in synucleinopathies. Important...

Frontiers in Neuroscience, 2015

Alpha-synuclein is a presynaptic protein expressed throughout the central nervous system, and it is the main component of Lewy bodies, one of the histopathological features of Parkinson's disease (PD) which is a progressive and irreversible neurodegenerative disorder. The conformational flexibility of α-synuclein allows it to adopt different conformations, i.e., bound to membranes or form aggregates, the oligomers are believed to be the more toxic species. In this review, we will focus on two major features of α-synuclein, transmission and toxicity, that could help to understand the pathological characteristics of PD. One important feature of α-synuclein is its ability to be transmitted from neuron to neuron using mechanisms such as endocytosis, plasma membrane penetration or through exosomes, thus propagating the Lewy body pathology to different brain regions thereby contributing to the progressiveness of PD. The second feature of α-synuclein is that it confers cytotoxicity to recipient cells, principally when it is in an oligomeric state. This form causes mitochondrial dysfunction, endoplasmic reticulum stress, oxidative stress, proteasome impairment, disruption of plasma membrane and pore formation that lead to apoptosis pathway activation and consequent cell death. The complexity of α-synuclein oligomerization and formation of toxic species could be a major factor for the irreversibility of PD and could also explain the lack of successful therapies to halt the disease.

Movement Disorders, 2011

Genetic studies of Parkinson's disease over the last decade or more have revolutionized our understanding of this condition. a-Synuclein was the first gene to be linked to Parkinson's disease, and is arguably the most important: the protein is the principal constituent of Lewy bodies, and variation at its locus is the major genetic risk factor for sporadic disease. Intriguingly, duplications and triplications of the locus, as well as point mutations, cause familial disease. Therefore , subtle alterations of a-synuclein expression can manifest with a dramatic phenotype. We outline the clinical impact of a-synuclein locus multiplications, and the implications that this has for Parkinson's disease pathogenesis. Finally, we discuss potential strategies for disease-modifying therapies for this currently incurable disorder. V

The pathogenesis of many neurodegenerative disorders arises in association with the misfolding and accumulation of a wide variety of proteins. Much emphasis has been placed on understanding the nature of these protein accumulations, including their composition, the process by which they are formed and the physiological impact they impose at cellular and, ultimately, organismal levels. Alpha-synuclein (ASYN) is the major component of protein inclusions known as Lewy bodies and Lewy neurites, which are the typical pathological hallmarks in disorders referred to as synucleinopathies. In addition, mutations or multiplications in the gene encoding for ASYN have also been shown to cause familial cases of PD, the most common synucleinopathy. Although the precise function of ASYN remains unclear, it appears to be involved in a vast array of cellular processes. Here, we review, in depth, a spectrum of cellular and molecular mechanisms that have been implicated in synucleinopathies. Importantly, detailed understanding of the biology/pathobiology of ASYN may enable the development of novel avenues for diagnosis and/or therapeutic intervention in synucleinopathies.

2003

α-Synuclein (αSN) brain pathology is a conspicuous feature of several neurodegenerative diseases. These include prevalent conditions such as Parkinson's disease (PD), dementia with Lewy bodies (DLB), and the Lewy body variant of Alzheimer's disease (LBVAD), as well as rarer conditions including multiple systems atrophy (MSA), and neurodegeneration with brain iron accumulation type-1 (NBIA-1). Common in these diseases, some referred to as α-synucleinopathies, are microscopic proteinaceous insoluble inclusions in neurons and glia that are composed largely of fibrillar aggregates of αSN. This molecular form of αSN contrasts sharply with normal αSN, which is an abundant soluble presynaptic protein in brain neurons. αSN is a highly conserved protein in vertebrates and only seven of its 140 amino acids differ between human and mouse. Flies lack an αSN gene. Implicated in neurotoxicity are two αSN mutants (A53T and A30P) that cause extremely rare familial forms of PD, αSN fibrils and protofibrils, soluble protein complexes of αSN with 14-3-3 protein, and phosphorylated, nitrosylated, and ubiquitylated αSN species. Unlike rare forms of fPD caused by mutations in αSN, disease mechanisms in most α-synucleinopathies implicate wildtype αSN and seem to converge around oxidative damage and impairments in protein catabolism. It is not known whether these causalities involve αSN from the beginning, but defects in the handling of this protein seem to contribute to disease progression because accumulation of toxic αSN forms damage neurons. Here, we summarize the main structural features of αSN and its functions, and discuss the molecular αSN species implicated in human disease and transgenic animal models of α-synucleinopathy in fly and rodents. 

Molecular Neurobiology, 2013

The discovery of α-synuclein has had profound implications concerning our understanding of Parkinson's disease (PD) and other neurodegenerative disorders characterized by α-synuclein accumulation. In fact, as compared with pre-α-synuclein times, a "new" PD can now be described as a whole-body disease in which a progressive spreading of α-synuclein pathology underlies a wide spectrum of motor as well as nonmotor clinical manifestations. Not only is α-synuclein accumulation a pathological hallmark of human α-synucleinopathies but increased protein levels are sufficient to trigger neurodegenerative processes. α-Synuclein elevations could also be a mechanism by which disease risk factors (e.g., aging) increase neuronal vulnerability to degeneration. An important corollary to the role of enhanced α-synuclein in PD pathogenesis is the possibility of developing α-synuclein-based biomarkers and new therapeutics aimed at suppressing α-synuclein expression. The use of in vitro and in vivo experimental models, including transgenic mice overexpressing α-synuclein and animals with viral vector-mediated α-synuclein transduction, has helped clarify pathogenetic mechanisms and therapeutic strategies involving α-synuclein. These models are not devoid of significant limitations, however. Therefore, further pursuit of new clues on the cause and treatment of PD in this post-α-synuclein era would benefit substantially from the development of improved research paradigms of αsynuclein elevation.

Journal of Biological Chemistry, 2018

Edited by Paul E. Fraser Parkinson's disease (PD) and multiple system atrophy (MSA) are distinct clinical syndromes characterized by the pathological accumulation of ␣-synuclein (␣-syn) protein fibrils in neurons and glial cells. These disorders and other neurodegenerative diseases may progress via prion-like mechanisms. The prion model of propagation predicts the existence of "strains" that link pathological aggregate structure and neuropathology. Prion strains are aggregated conformers that stably propagate in vivo and cause disease with defined incubation times and patterns of neuropathology. Indeed, tau prions have been well defined, and research suggests that both ␣-syn and ␤-amyloid may also form strains. However, there is a lack of studies characterizing PDversus MSA-derived ␣-syn strains or demonstrating stable propagation of these unique conformers between cells or animals. To fill this gap, we used an assay based on FRET that exploits a HEK293T "biosensor" cell line stably expressing ␣-syn (A53T)-CFP/YFP fusion proteins to detect ␣-syn seeds in brain extracts from PD and MSA patients. Both soluble and insoluble fractions of MSA extracts had robust seeding activity, whereas only the insoluble fractions of PD extracts displayed seeding activity. The morphology of MSA-seeded inclusions differed from PD-seeded inclusions. These differences persisted upon propagation of aggregation to secondgeneration biosensor cells. We conclude that PD and MSA feature ␣-syn conformers with very distinct biochemical properties that can be transmitted to ␣-syn monomers in a cell system. These findings are consistent with the idea that distinct ␣-syn strains underlie PD and MSA and offer possible directions for synucleinopathy diagnosis.

A variety of neurodegenerative disorders are classified as synucleinopathies based on the presence of prominent α-synuclein pathology. These diseases include Parkinson disease (PD) and dementia with Lewy bodies (with neuronal Lewy body formation) and multiple system atrophy (with glial cytoplasmic inclusions). The normal function of α-synuclein includes regulation of pre-synaptic vesicles. Autosomal dominant PD can be due to coding mutations or multiplications of the α-synuclein gene (SNCA). The coding mutations are thought to lead to a gain of function, in particular acceleration of the formation of proto-fibrils. Duplications and triplications of SNCA lead to autosomal dominant PD with a gene dosage effect on age of onset and clinical severity; variants in the SNCA promoter which lead to an upregulation of SNCA expression are associated with an increased risk of sporadic PD.

Frontiers in neurology, 2018

Over the last two decades, many experimental and clinical studies have provided solid evidence that alpha-synuclein (α-syn), a small, natively unfolded protein, is closely related to Parkinson's disease (PD) pathology. To provide an overview on the different roles of this protein, here we propose a synopsis of seminal and recent studies that explored the many aspects of α-syn. Ranging from the physiological functions to its neurodegenerative potential, the relationship with the possible pathogenesis of PD will be discussed. Close attention will be paid on early cellular and molecular alterations associated with the presence of α-syn aggregates.