Cell Biology and Pathophysiology of α-Synuclein

Burré, Jacqueline; Sharma, Manu; Südhof, Thomas C.

doi:10.1101/cshperspect.a024091

Cited by 445 publications

(445 citation statements)

References 333 publications

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“…The majority of research focusing on α-synuclein misfolding in animal and cellular models of synucleinopathy has relied on recombinant or synthetic α-synuclein that is fibrillized in the laboratory (reviewed in refs. [17][18][19]. To profile the infectivity of synthetic fibrils, we aggregated recombinant WT, A30P, E46K, and A53T α-synuclein and tested serial dilutions of these fibrils for their ability to infect the nine α-synuclein−YFP cell lines (Fig.…”

Section: Msa Prions Retain Exquisite Selectivity In α-Synuclein-yfp Cmentioning

confidence: 99%

Familial Parkinson’s point mutation abolishes multiple system atrophy prion replication

Woerman

Kazmi

Patel

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

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In the neurodegenerative disease multiple system atrophy (MSA), α-synuclein misfolds into a self-templating conformation to become a prion. To compare the biological activity of α-synuclein prions in MSA and Parkinson's disease (PD), we developed nine α-synuclein−YFP cell lines expressing point mutations responsible for inherited PD. MSA prions robustly infected wild-type, A30P, and A53T α-synuclein-YFP cells, but they were unable to replicate in cells expressing the E46K mutation. Coexpression of the A53T and E46K mutations was unable to rescue MSA prion infection in vitro, establishing that MSA α-synuclein prions are conformationally distinct from the misfolded α-synuclein in PD patients. This observation may have profound implications for developing treatments for neurodegenerative diseases.ultiple system atrophy (MSA) is a rapidly progressing neurodegenerative disease resulting in dysfunction of the autonomic nervous system and disrupted motor function. The pathological hallmark of MSA is the presence of α-synuclein aggregates that coalesce into glial cytoplasmic inclusions (GCIs) in oligodendrocytes (1). MSA is one of four synucleinopathies, the other three being Parkinson's disease (PD), Parkinson's disease with dementia (PDD), and dementia with Lewy bodies (DLB). In PD, PDD, and DLB patients, α-synuclein accumulates in neurons as Lewy bodies and Lewy neurites (2). Recent studies demonstrate that MSA is unequivocally caused by α-synuclein prions, which are misfolded proteins that undergo self-propagation and are capable of transmitting disease to transgenic (Tg) mice (3-6). Using TgM83 +/− mice, which express human α-synuclein with the familial A53T mutation, both intracranial (3, 5) and peripheral inoculation (6) of brain homogenate from a total of 17 MSA patients induced neurological disease in the animals. In addition, α-synuclein prions isolated from MSA patients propagated in cultured HEK cells that express mutant human α-synuclein*A53T fused to YFP (α-syn140*A53T−YFP) (4). While PD transmission studies have induced α-synuclein neuropathology (7-9), attempts to transmit disease to TgM83 +/− mice or to infect α-syn140*A53T−YFP cells have been unsuccessful (5), suggesting that distinct conformations of misfolded α-synuclein or α-synuclein prion strains may be responsible for these diseases.To study the strain-specific properties of α-synuclein prions in MSA patients and to reconcile the differences between PD and MSA prions, we conducted a series of studies to investigate the effect of inherited PD point mutations on MSA prion replication. In addition to the original WT (α-syn140-YFP) and α-syn140*A53T-YFP cells first reported in 2015 (4), we generated seven additional HEK cell lines expressing single mutations (A30P and E46K), double mutations (A30P,A53T and E46K,A53T), and truncated α-synuclein*A53T (residues 1-95, 1-97, and 29-97). After measuring MSA prion infection in the WT, A30P, and A53T cell lines, we were surprised to observe that the E46K mutation prevented the replication of MSA prions in vi...

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Section: Msa Prions Retain Exquisite Selectivity In α-Synuclein-yfp Cmentioning

confidence: 99%

Familial Parkinson’s point mutation abolishes multiple system atrophy prion replication

Woerman

Kazmi

Patel

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

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“…However, the precise role of α‐Syn to these processes remains uncertain (Burre et al . ). Surprisingly, the normal cellular physiology and synaptic function of α‐Syn knockout mice suggest that the absence of α‐Syn may not be reason enough for severe systemic dysfunction (Abeliovich et al .…”

Section: Putative Functions and Dysfunction Of α‐Synmentioning

confidence: 97%

In vitro models of synucleinopathies: informing on molecular mechanisms and protective strategies

Marvian

Koss

Aliakbari

et al. 2019

Journal of Neurochemistry

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Alpha‐synuclein (α‐Syn) is a central player in Parkinson's disease (PD) and in a spectrum of neurodegenerative diseases collectively known as synucleinopathies. The protein was first associated with PD just over 20 years ago, when it was found to (i) be a major component of Lewy bodies and (ii) to be also associated with familial forms of PD. The characterization of α‐Syn pathology has been achieved through postmortem studies of human brains. However, the identification of toxic mechanisms associated with α‐Syn was only achieved through the use of experimental models. In vitro models are highly accessible, enable relatively rapid studies, and have been extensively employed to address α‐Syn‐associated neurodegeneration. Given the diversity of models used and the outcomes of the studies, a cumulative and comprehensive perspective emerges as indispensable to pave the way for further investigations. Here, we subdivided in vitro models of α‐Syn pathology into three major types: (i) models simulating α‐Syn fibrillization and the formation of different aggregated structures in vitro, (ii) models based on the intracellular expression of α‐Syn, reporting on pathogenic conditions and cellular dysfunctions induced, and (iii) models using extracellular treatment with α‐Syn aggregated species, reporting on sites of interaction and their downstream consequences. In summary, we review the underlying molecular mechanisms discovered and categorize protective strategies, in order to pave the way for future studies and the identification of effective therapeutic strategies. This article is part of the Special Issue “Synuclein”.

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“…However, the function and expression of synaptic proteins such as synapsins can severely diverge within different neuronal subtypes, suggesting that α‐syn may also exhibit a different action profile in relation to the specific cellular entourage. The fact that α‐syn contributes to the maintenance of synaptic homeostasis and neurotransmitter turnover by regulating the dopamine transporter (DAT) and vesicular monoamine transporter 2 (VMAT2) in one of the most vulnerable neuronal population such as dopaminergic neurons seems to be in line with this hypothesis . α‐Syn can also influence the neuronal protein trafficking by interacting with cytoskeletal components.…”

Section: A Brief Overview On the Synaptic Functions Of α‐Synmentioning

confidence: 83%

“…α‐Syn can also influence the neuronal protein trafficking by interacting with cytoskeletal components. Moreover, it can act as a molecular chaperone and promote lipid membrane curvature, thus facilitating the generation of small vesicles such as synaptic vesicles…”

Section: A Brief Overview On the Synaptic Functions Of α‐Synmentioning

confidence: 99%

“…At present, we know that some of these, such as C‐terminal truncation, occur early, as cleaved α‐syn composes the core of LB and promotes full‐length α‐syn aggregation. Contrarily, some others, such as Ser129 phosphorylation, intervene late, probably when the formation of aggregates has already initiated and may be considered a possible consequence of α‐syn‐induced cell damage . Unfortunately, we cannot predict whether these modifications could hamper the action of strategies aimed at reducing α‐syn aggregation.…”

Section: The Good and Bad Of Therapeutic Strategies Targeting α‐Syn Amentioning

confidence: 99%

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The good and bad of therapeutic strategies that directly target α‐synuclein

et al. 2019

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Synucleinopathies are neurodegenerative diseases characterized by the accumulation of either neuronal/axonal or glial insoluble proteinaceous aggregates mainly composed of α‐synuclein (α‐syn). Among them, the most common disorders are Parkinson's disease, dementia with Lewy bodies, multiple system atrophy, and some forms of familial parkinsonism. Both α‐syn fibrils and oligomers have been found to exert toxic effects on neurons or oligodendroglial cells, can activate neuroinflammatory responses, and mediate the spreading of α‐syn pathology. This poses the question of which is the most toxic α‐syn species. What is worst, α‐syn appears as a very peculiar protein, exerting multiple physiological functions in neurons, especially at synapses, but without acquiring a stable tertiary structure. Its conformation is particularly plastic, and the protein can exist in a natively unfolded state (mainly in solution), partially α‐helical folded state (when it interacts with biological membranes), or oligomeric state (tetramers or dimers with debated functional profile). The extent of α‐syn expression impinges on the resilience of neuronal cells, as multiplications of its gene locus, or overexpression, can cause neurodegeneration and onset of motor phenotype. For these reasons, one of the main challenges in the field of synucleinopathies, which still nowadays can only be managed by symptomatic therapies, has been the development of strategies aimed at reducing α‐syn levels, oligomer formation, fibrillation, or cell‐to‐cell transmission. This review resumes the therapeutic approaches that have been proposed or are under development to counteract α‐syn pathology by direct targeting of this protein and discuss their pros and cons in relation to the current state‐of‐the‐art α‐syn biology.

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Cell Biology and Pathophysiology of α-Synuclein

Cited by 445 publications

References 333 publications

Familial Parkinson’s point mutation abolishes multiple system atrophy prion replication

Familial Parkinson’s point mutation abolishes multiple system atrophy prion replication

In vitro models of synucleinopathies: informing on molecular mechanisms and protective strategies

The good and bad of therapeutic strategies that directly target α‐synuclein

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