α-Synuclein Cooperates with CSPα in Preventing Neurodegeneration

Chandra, Sreeganga S.; Gallardo, Gilbert; Fernández‐Chacón, Rafael; Schlüter, Oliver M.; Südhof, Thomas C.

doi:10.1016/j.cell.2005.09.028

Cited by 901 publications

(929 citation statements)

References 55 publications

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“…α ‐Synuclein is known to modulate synaptic pathology in mice, at least in part through interactions with another synaptic protein, CSP‐ α (Chandra et al. 2005). Mutations in CSP ‐ α lead to a dominant adult form of NCL, Kuf's disease (CLN4 (Nosková et al.…”

Section: Discussionmentioning

confidence: 99%

Molecular neuropathology of the synapse in sheep with CLN5 Batten disease

et al. 2015

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AimsSynapses represent a major pathological target across a broad range of neurodegenerative conditions. Recent studies addressing molecular mechanisms regulating synaptic vulnerability and degeneration have relied heavily on invertebrate and mouse models. Whether similar molecular neuropathological changes underpin synaptic breakdown in large animal models and in human patients with neurodegenerative disease remains unclear. We therefore investigated whether molecular regulators of synaptic pathophysiology, previously identified in Drosophila and mouse models, are similarly present and modified in the brain of sheep with CLN5 Batten disease.MethodsGross neuropathological analysis of CLN5 Batten disease sheep and controls was used alongside postmortem MRI imaging to identify affected brain regions. Synaptosome preparations were then generated and quantitative fluorescent Western blotting used to determine and compare levels of synaptic proteins.ResultsThe cortex was particularly affected by regional neurodegeneration and synaptic loss in CLN5 sheep, whilst the cerebellum was relatively spared. Quantitative assessment of the protein content of synaptosome preparations revealed significant changes in levels of seven out of eight synaptic neurodegeneration proteins investigated in the motor cortex, but not cerebellum, of CLN5 sheep (α‐synuclein, CSP‐α, neurofascin, ROCK2, calretinin, SIRT2, and UBR4).ConclusionsSynaptic pathology is a robust correlate of region‐specific neurodegeneration in the brain of CLN5 sheep, driven by molecular pathways similar to those reported in Drosophila and rodent models. Thus, large animal models, such as sheep, represent ideal translational systems to develop and test therapeutics aimed at delaying or halting synaptic pathology for a range of human neurodegenerative conditions.

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Section: Discussionmentioning

confidence: 99%

Molecular neuropathology of the synapse in sheep with CLN5 Batten disease

et al. 2015

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“…However, on the other side, there is strong evidence that a-synuclein is a positive modulator of SNAREcomplex assembly, as shown in mice with a knockout of the cysteine-string protein a (CSPa). In these mice a severe neurodegenerative phenotype is seen that has been linked to a decrease in the chaperoning of the SNAP-25 protein, which in turn decreases the efficacy of the SNAREcomplex assembly and exocytosis [26][27][28]. Intriguingly, there was an almost complete rescue of this toxic phenotype when a-synuclein was overexpressed, and a positive regulatory effect of a-synuclein on exocytosis was therefore proposed.…”

Section: A-synuclein In Synaptic Vesicle Exocytosismentioning

confidence: 99%

“…Intriguingly, there was an almost complete rescue of this toxic phenotype when a-synuclein was overexpressed, and a positive regulatory effect of a-synuclein on exocytosis was therefore proposed. A simple substitution of CSPa chaperone activity by a-synuclein was not seen, and it was therefore suggested that a-synuclein might instead be able to stabilize SNAP-25 within the SNARE complex and thus make the protein less prone to degradation [27]. However, other and more subtle downstream effects could also come into play.…”

Section: A-synuclein In Synaptic Vesicle Exocytosismentioning

confidence: 99%

α-Synuclein – Regulator of Exocytosis, Endocytosis, or Both?

Lautenschläger

Kaminski

Schierle

2017

Trends in Cell Biology

119

124

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a-Synuclein is known as a presynaptic protein that binds to small synaptic vesicles. Recent studies suggest that a-synuclein is not only attracted to these tiny and therewith highly curved membranes, but that in fact the sensing and regulation of membrane curvature is part of its physiological function. Moreover, recent studies have suggested that a-synuclein plays a role in the endocytosis of synaptic vesicles, and have provided support for a function of a-synuclein during exo-and endocytosis in which curvature sensing and membrane stabilization are crucial steps. This review aims to highlight recent research in the field and adds a new picture on the function of a-synuclein in maintaining synaptic homeostasis upon intense and repetitive neuronal activity.

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“…In the presynaptic compartment ␣-synuclein has been proposed to participate both in the exocytic process (Chandra et al, 2005) and in the regulation of the synaptic vesicle pools. However, conflicting results have been reported in the knock-out mice.…”

Section: Introductionmentioning

confidence: 99%

α-Synuclein and Its A30P Mutant Affect Actin Cytoskeletal Structure and Dynamics

Sousa

Bellani

Giannandrea

et al. 2009

MBoC

105

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The function of ␣-synuclein, a soluble protein abundant in the brain and concentrated at presynaptic terminals, is still undefined. Yet, ␣-synuclein overexpression and the expression of its A30P mutant are associated with familial Parkinson's disease. Working in cell-free conditions, in two cell lines as well as in primary neurons we demonstrate that ␣-synuclein and its A30P mutant have different effects on actin polymerization. Wild-type ␣-synuclein binds actin, slows down its polymerization and accelerates its depolymerization, probably by monomer sequestration; A30P mutant ␣-synuclein increases the rate of actin polymerization and disrupts the cytoskeleton during reassembly of actin filaments. Consequently, in cells expressing mutant ␣-synuclein, cytoskeleton-dependent processes, such as cell migration, are inhibited, while exo-and endocytic traffic is altered. In hippocampal neurons from mice carrying a deletion of the ␣-synuclein gene, electroporation of wild-type ␣-synuclein increases actin instability during remodeling, with growth of lamellipodia-like structures and apparent cell enlargement, whereas A30P ␣-synuclein induces discrete actin-rich foci during cytoskeleton reassembly. In conclusion, ␣-synuclein appears to play a major role in actin cytoskeletal dynamics and various aspects of microfilament function. Actin cytoskeletal disruption induced by the A30P mutant might alter various cellular processes and thereby play a role in the pathogenesis of neurodegeneration.

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α-Synuclein Cooperates with CSPα in Preventing Neurodegeneration

Cited by 901 publications

References 55 publications

Molecular neuropathology of the synapse in sheep with CLN5 Batten disease

Molecular neuropathology of the synapse in sheep with CLN5 Batten disease

α-Synuclein – Regulator of Exocytosis, Endocytosis, or Both?

α-Synuclein and Its A30P Mutant Affect Actin Cytoskeletal Structure and Dynamics

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