Contrasting Effects of α-Synuclein and γ-Synuclein on the Phenotype of Cysteine String Protein α (CSPα) Null Mutant Mice Suggest Distinct Function of these Proteins in Neuronal Synapses

Ninkina, Natalia; Peters, Owen M.; Connor-Robson, Natalie; Лыткина, О. А.; Sharfeddin, Essam; Buchman, Vladimir L.

doi:10.1074/jbc.m112.422402

Cited by 28 publications

(24 citation statements)

References 37 publications

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“…In particular, the hydrophilic C-terminus of α-synuclein appears to interact with v-SNARE synaptobrevin 2 (Burre et al, 2010). Consistent with a requirement for the C-terminus of α-synuclein to interact with synaptobrevin, γ-synuclein, which diverges in sequence from α- at the C-terminus, does not rescue the loss of CSPα (Ninkina et al, 2012). In contrast to the role of CSPα as chaperone for SNAP-25, α-synuclein thus appears to have a role in SNARE complex formation.…”

Section: The Role Of Synuclein In Neurotransmitter Releasementioning

confidence: 86%

The Function of α-Synuclein

Bendor

Logan

Edwards

2013

Neuron

742

613

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Human genetics has indicated a causal role for the protein α-synuclein in the pathogenesis of familial Parkinson’s disease (PD), and the aggregation of synuclein in essentially all patients with PD suggests a central role for this protein in the sporadic disorder. Indeed, the accumulation of misfolded α-synuclein now defines multiple forms of neural degeneration. Like many of the proteins that accumulate in other neurodegenerative disorders, however, the normal function of synuclein remains poorly understood. α-Synuclein localizes specifically to the nerve terminal and inhibits neurotransmitter release when over-expressed, but the knockout has a modest effect on synaptic transmission, suggesting alternative presynaptic roles. Natively unstructured, synuclein adopts a helical conformation on membrane binding and recent work suggests a role in membrane remodeling. In neural degeneration, synuclein misfolds and aggregates as a β-sheet. Multiple observations now suggest propagation of the misfolded protein as a prion, providing a mechanism for the spread of degeneration through the neuraxis. However, the factors that trigger the original misfolding remain unknown.

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Section: The Role Of Synuclein In Neurotransmitter Releasementioning

confidence: 86%

The Function of α-Synuclein

Bendor

Logan

Edwards

2013

Neuron

742

613

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show abstract

“…, ; Ninkina et al . ). However, the exact role that α‐syn plays in these mechanisms remains uncertain.…”

Section: Basic α‐Synuclein Biologymentioning

confidence: 97%

Sorting out release, uptake and processing of alpha‐synuclein during prion‐like spread of pathology

Tyson

Steiner

Brundin

2016

Journal of Neurochemistry

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Parkinson’s disease is a progressive neurological disorder that is characterized by the formation of intracellular protein inclusion bodies composed primarily of a misfolded and aggregated form of the protein α-synuclein. There is growing evidence that supports the prion-like hypothesis of α-synuclein progression. This hypothesis postulates that α-synuclein is a prion-like pathological agent and is responsible for the progression of Parkinson pathology in the brain. Potential misfolding or aggregation of α-synuclein that might occur in the peripheral nervous system as a result of some insult, environmental or genetic (or more likely a combination of both) that might spread into the midbrain, eventually causing degeneration of the neurons in the substantia nigra. As the diseases progresses further it is likely that α-synuclein pathology continues to spread throughout the brain, including the cortex, leading to deterioration of cognition and higher brain functions. While it is unknown why α-synuclein initially misfolds and aggregates, a great deal has been learnt about how the cell handles aberrant α-synuclein assemblies. In this review we focus on these mechanisms and discuss them in an attempt to define the role that they might play in the propagation of misfolded α-synuclein from cell-to-cell.

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“…It has been speculated that in the nervous system γ-synuclein is involved in modulation of monoamine transporters [2,3], cytoprotection [4,5], chaperone activity [6], microtubule regulation and microtubule mediated organelle trafficking [7]. However, the exact mechanisms and consequences of this involvement are to be resolved.…”

Section: Introductionmentioning

confidence: 99%

Differential involvement of the gamma-synuclein in cognitive abilities on the model of knockout mice

et al. 2013

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BackgroundGamma-synuclein is a member of the synuclein family of cytoplasmic, predominantly neuron-specific proteins. Despite numerous evidences for the importance of gamma-synuclein in the control of monoamine homeostasis, cytoskeleton reorganization and chaperone activity, its role in the regulation of cognitive behavior still remain unknown. Our previous study revealed that gamma-synuclein knockout mice are characterized by high habituation scores. Since a number of processes including spatial memory of the environment may affect habituation, in the present study we have carried out behavioral evaluation of spatial and working memory in gamma-synuclein knockout mice.ResultsInactivation of gamma-synuclein gene led to the improvement of working memory in mice as revealed by passive and active avoidance tests. At the same time behavioral tests, designed to assess spatial learning and memory (Morris water maze and Object location tests), showed no differences between gamma-synuclein knockouts and wild type mice.ConclusionsThese findings indicate that young mice with targeted inactivation of gamma-synuclein gene have improved working memory, but not spatial learning and memory. Our results suggest that gamma-synuclein is directly involved in the regulation of cognitive functions.

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Contrasting Effects of α-Synuclein and γ-Synuclein on the Phenotype of Cysteine String Protein α (CSPα) Null Mutant Mice Suggest Distinct Function of these Proteins in Neuronal Synapses

Cited by 28 publications

References 37 publications

The Function of α-Synuclein

The Function of α-Synuclein

Sorting out release, uptake and processing of alpha‐synuclein during prion‐like spread of pathology

Differential involvement of the gamma-synuclein in cognitive abilities on the model of knockout mice

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