Beta- And Gamma-Synucleins Modulate Synaptic Vesicle-Binding of Alpha-Synuclein

Carnazza, Kathryn E.; Komer, Lauren; Pineda, André; Na, Yoonmi; Ramlall, Trudy F.; Buchman, Vladimir L.; Eliezer, David; Sharma, Manu; Burré, Jacqueline

doi:10.1101/2020.11.19.390419

Cited by 3 publications

(6 citation statements)

References 86 publications

(156 reference statements)

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“…Indeed, our data suggest that β-synuclein, via interaction with a number of vesicular and cytosolic proteins, can potentiate formation of various molecular complexes on the surface of synaptic vesicles. This is similar to α-synuclein, which is known to interact with a variety of proteins and function as a chaperone or scaffold for the assembly of multiprotein complexes on the surface of synaptic vesicles, implicating α-synuclein in a number of molecular processes at several stages of the synaptic vesicle cycle ( 45 , 46 , 47 , 48 ). However, potentiation of vesicular uptake is not included in the list of possible functions of α-synuclein or γ-synuclein, and therefore, they are unable to compensate for the loss of this particular function of β-synuclein.…”

Section: Resultsmentioning

confidence: 91%

“…All three members of the synuclein family can interact with phospholipids at the outer surface of synaptic vesicles via their conserved N-terminal repeat domain, but the number of functional multiprotein complexes each member can form on a given vesicle is limited. Moreover, results of the recent study ( 48 ) suggested that synucleins modulate each other's binding to synaptic vesicle–like membranes possibly via formation of heteromeric complexes. Such synuclein complexes attract different combination of other proteins than single synuclein-based complexes ( e.g.…”

Section: Resultsmentioning

confidence: 99%

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β-synuclein potentiates synaptic vesicle dopamine uptake and rescues dopaminergic neurons from MPTP-induced death in the absence of other synucleins

Ninkina

Millership

Peters

et al. 2021

Journal of Biological Chemistry

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Synucleins, a family of three proteins highly expressed in neurons, are predominantly known for the direct involvement of α-synuclein in the etiology and pathogenesis of Parkinson's and certain other neurodegenerative diseases, but their precise physiological functions are still not fully understood. Previous studies have demonstrated the importance of α-synuclein as a modulator of various mechanisms implicated in chemical neurotransmission, but information concerning the involvement of other synuclein family members, β-synuclein and γ-synuclein, in molecular processes within presynaptic terminals is limited. Here, we demonstrated that the vesicular monoamine transporter 2–dependent dopamine uptake by synaptic vesicles isolated from the striatum of mice lacking β-synuclein is significantly reduced. Reciprocally, reintroduction, either in vivo or in vitro , of β-synuclein but not α-synuclein or γ-synuclein improves uptake by triple α/β/γ-synuclein–deficient striatal vesicles. We also showed that the resistance of dopaminergic neurons of the substantia nigra pars compacta to subchronic administration of the Parkinson's disease–inducing prodrug 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine depends on the presence of β-synuclein but only when one or both other synucleins are absent. Furthermore, proteomic analysis of synuclein-deficient synaptic vesicles versus those containing only β-synuclein revealed differences in their protein compositions. We suggest that the observed potentiation of dopamine uptake by β-synuclein might be caused by different protein architecture of the synaptic vesicles. It is also feasible that such structural changes improve synaptic vesicle sequestration of 1-methyl-4-phenylpyridinium, a toxic metabolite of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine, which would explain why dopaminergic neurons expressing β-synuclein and lacking α-synuclein and/or γ-synuclein are resistant to this neurotoxin.

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Section: Resultsmentioning

confidence: 91%

Section: Resultsmentioning

confidence: 99%

β-synuclein potentiates synaptic vesicle dopamine uptake and rescues dopaminergic neurons from MPTP-induced death in the absence of other synucleins

Ninkina

Millership

Peters

et al. 2021

Journal of Biological Chemistry

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“…Lipid binding of the synucleins reflects functional compensation, whereby in the presence of αS, the membrane association of βS and γS was enhanced. Concomitantly, the presence of βS and γS attenuated the membrane association of αS [ 54 ]. Taken together, these studies suggest that lipid binding is an evolutionary conserved biological role of βS.…”

Section: The Function Of β-Synucleinmentioning

confidence: 99%

β-Synuclein: An Enigmatic Protein with Diverse Functionality

Hayashi¹,

Carver²

2022

Biomolecules

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α-Synuclein (αS) is a small, unstructured, presynaptic protein expressed in the brain. Its aggregated form is a major component of Lewy bodies, the large proteinaceous deposits in Parkinson’s disease. The closely related protein, β-Synuclein (βS), is co-expressed with αS. In vitro, βS acts as a molecular chaperone to inhibit αS aggregation. As a result of this assignation, βS has been largely understudied in comparison to αS. However, recent reports suggest that βS promotes neurotoxicity, implying that βS is involved in other cellular pathways with functions independent of αS. Here, we review the current literature pertaining to human βS in order to understand better the role of βS in homeostasis and pathology. Firstly, the structure of βS is discussed. Secondly, the ability of βS to (i) act as a molecular chaperone; (ii) regulate synaptic function, lipid binding, and the nigrostriatal dopaminergic system; (iii) mediate apoptosis; (iv) participate in protein degradation pathways; (v) modulate intracellular metal levels; and (vi) promote cellular toxicity and protein aggregation is explored. Thirdly, the P123H and V70M mutations of βS, which are associated with dementia with Lewy bodies, are discussed. Finally, the importance of post-translational modifications on the structure and function of βS is reviewed. Overall, it is concluded that βS has both synergistic and antagonistic interactions with αS, but it may also possess important cellular functions independent of αS.

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“…Synucleins are important for the synaptic transmission and circulation of synaptic vesicles [ 22 , 23 , 24 , 25 , 26 , 27 ]. Alpha-synuclein modulates the release of neurotransmitters from presynaptic terminals by binding and clustering synaptic vesicles and chaperoning the soluble N-ethylmaleimide-sensitive factor attachment protein receptor (SNARE) complex assembly by binding to the protein synaptobrevin-2 (VAMP2) [ 28 , 29 ] whereas beta-synuclein and gamma-synuclein modulate the synaptic vesicular binding of alpha-synuclein and thus reduce the synaptic physiological activity of alpha-synuclein [ 30 , 31 ] ( Table 1 ). Moreover, in vitro and in vivo experiments have revealed that all three members of the synuclein family have chaperone activity [ 32 , 33 , 34 ].…”

Section: Synuclein Structure and Functionsmentioning

confidence: 99%

“…Alpha-, beta-, and gamma-synucleins can bind to the dopamine transporter (DAT) and modulate its delivery to the synaptic membrane, thereby affecting dopamine neurotransmitter reuptake [ 11 , 31 , 35 ]. In turn, it has been shown through protein–protein interactions that alpha-synuclein can affect DAT activity and this effect is regulated by the gamma-synuclein concentration [ 36 , 37 , 38 ].…”

Section: Synuclein Structure and Functionsmentioning

confidence: 99%

Synuclein Proteins in MPTP-Induced Death of Substantia Nigra Pars Compacta Dopaminergic Neurons

et al. 2022

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Parkinson’s disease (PD) is one of the key neurodegenerative disorders caused by a dopamine deficiency in the striatum due to the death of dopaminergic (DA) neurons of the substantia nigra pars compacta. The initially discovered A53T mutation in the alpha-synuclein gene was linked to the formation of cytotoxic aggregates: Lewy bodies in the DA neurons of PD patients. Further research has contributed to the discovery of beta- and gamma-synucleins, which presumably compensate for the functional loss of either member of the synuclein family. Here, we review research from 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) toxicity models and various synuclein-knockout animals. We conclude that the differences in the sensitivity of the synuclein-knockout animals compared with the MPTP neurotoxin are due to the ontogenetic selection of early neurons followed by a compensatory effect of beta-synuclein, which optimizes dopamine capture in the synapses. Triple-knockout synuclein studies have confirmed the higher sensitivity of DA neurons to the toxic effects of MPTP. Nonetheless, beta-synuclein could modulate the alpha-synuclein function, preventing its aggregation and loss of function. Overall, the use of knockout animals has helped to solve the riddle of synuclein functions, and these proteins could be promising molecular targets for the development of therapies that are aimed at optimizing the synaptic function of dopaminergic neurons.

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Beta- And Gamma-Synucleins Modulate Synaptic Vesicle-Binding of Alpha-Synuclein

Cited by 3 publications

References 86 publications

β-synuclein potentiates synaptic vesicle dopamine uptake and rescues dopaminergic neurons from MPTP-induced death in the absence of other synucleins

β-synuclein potentiates synaptic vesicle dopamine uptake and rescues dopaminergic neurons from MPTP-induced death in the absence of other synucleins

β-Synuclein: An Enigmatic Protein with Diverse Functionality

Synuclein Proteins in MPTP-Induced Death of Substantia Nigra Pars Compacta Dopaminergic Neurons

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