Double-knockout mice for α- and β-synucleins: Effect on synaptic functions

Chandra, Sreeganga S.; Fornai, Francesco; Kwon, Hyung Bae; Yazdani, Umar; Atasoy, Deniz; Liu, Xinran; Hammer, Robert E.; Battaglia, Giuseppe; German, Dwight C.; Castillo, Pablo E.; Südhof, Thomas C.

doi:10.1073/pnas.0406283101

Cited by 406 publications

(379 citation statements)

References 38 publications

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“…Indeed, ␣S has been observed to influence the critical micelle concentration of SDS (42), to directly perturb lipid bilayer structure in vitro (63)(64)(65)(66), and even to remodel membrane topology (67,68). Such activities could be consistent with a number of studies showing that ␣S can influence the neurotransmitter release at synapses (69,70) and may be directly involved in vesicle fusion pathways (71)(72)(73). The potential role of the interconversion of the protein between the broken and extended helix forms in mediating such effects remains to be explored, but we have proposed one specific model (62) in which this conversion process may play a role in regulating synaptic vesicle fusion by allowing the protein to bridge between different membranes (Fig.…”

Section: Discussionsupporting

confidence: 64%

The Lipid-binding Domain of Wild Type and Mutant α-Synuclein

Georgieva

Ramlall

Borbat

et al. 2010

Journal of Biological Chemistry

132

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␣-Synuclein (␣S) is linked to Parkinson disease through its deposition in an amyloid fibril form within Lewy Body deposits, and by the existence of three ␣S point mutations that lead to early onset autosomal dominant Parkinsonism. The normal function of ␣S is thought to be linked to the ability of the protein to bind to the surface of synaptic vesicles. Upon binding to vesicles, ␣S undergoes a structural reorganization from a dynamic and disordered ensemble to a conformation consisting of a long extended helix. In the presence of small spheroidal detergent micelles, however, this extended helix conformation can convert into a broken helix state, in which a region near the middle of the helix unwinds to form a linker between the two resulting separated helices. Membrane-bound conformations of ␣S likely mediate the function of the protein, but may also play a role in the aggregation and toxicity of the protein. Here we have undertaken a study of the effects of the three known PD-linked mutations on the detergent-and membrane-bound conformations of ␣S, as well as factors that govern the transition of the protein between the extended helix and broken helix states. Using pulsed dipolar ESR measurements of distances up to 8.7 nm, we show that all three PD-linked ␣S mutants retain the ability to transition from the broken helix to the extended helix conformation. In addition, we find that the ratio of protein to detergent, rather than just the absolute detergent concentration, determines whether the protein adopts the broken or extended helix conformation.Since its initial discovery as a protein enriched in the electric organ of the Pacific electric ray, Torpedo californica (1), the protein ␣-synuclein has been progressively associated with a role in neurodegeneration in humans, starting with its identification as the precursor protein of a non-amyloid-␤ peptide component of amyloid plaques (the so-called NAC peptide) (2) and culminating in its discovery as the first gene product to be linked to familial Parkinson disease (3) and its contemporaneous identification as the primary component of the fibrillary aggregates found in the hallmark Lewy body deposits associated with Parkinson (4).Subsequently, a great deal of effort has been made to clarify and understand the mechanisms by which ␣S causes neuronal degeneration, as well as to understand the normal functional roles of ␣S and how these are related to its role in disease (5, 6). Although aggregation of ␣S remains a key focus in these efforts, it remains possible that other, or additional, effects beyond the presence of various aggregated species of ␣S may be involved in the etiology of synuclein-associated PD. A key piece of the puzzle that remains unanswered is which of the various forms of ␣S that have been observed in vitro are involved in mediating the toxicity of the protein in vivo. In particular, although ␣S is highly disordered when isolated in solution in vitro (7-9) it is not clear to what extent this intrinsically disordered state is populated in vivo. Be...

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Section: Discussionsupporting

confidence: 64%

The Lipid-binding Domain of Wild Type and Mutant α-Synuclein

Georgieva

Ramlall

Borbat

et al. 2010

Journal of Biological Chemistry

132

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“…What is happening upon a-synuclein knockout? Here studies report decreased exocytosis [33,35,37,38], no change [36,39], or even increased exocytosis [40][41][42] (Table 2). However, these studies need to be interpreted with care because a-synuclein is not the only synuclein isoform, and loss of physiological function could possibly be compensated by b-or g-synuclein.…”

Section: Function Of A-synuclein On Synaptic Activity and Transmittermentioning

confidence: 63%

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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“…However, conflicting results have been reported in the knock-out mice. Depletion of the reserve pool of synaptic vesicles has been reported by one group (Cabin et al, 2002) but not by another (Chandra et al, 2004). Likewise, transmitter release from neurosecretory cells has been reported to be modulated by ␣-synuclein, either in a positive (Liu et al, 2004) or in a negative manner (Larsen et al, 2006).…”

Section: Introductionmentioning

confidence: 93%

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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Double-knockout mice for α- and β-synucleins: Effect on synaptic functions

Cited by 406 publications

References 38 publications

The Lipid-binding Domain of Wild Type and Mutant α-Synuclein

The Lipid-binding Domain of Wild Type and Mutant α-Synuclein

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

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

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