Alterations in the nigrostriatal system following conditional inactivation of α-synuclein in neurons of adult and aging mice

Ninkina, Natalia; Tarasova, Tatiana; Chaprov, Kirill; Roman, Andrei; Kukharsky, Michail S.; Колик, Л. Г.; Овчинников, Р. К.; Ustyugov, A. A.; Дурнев, А. Д.; Buchman, Vladimir L.

doi:10.1016/j.neurobiolaging.2020.02.026

Cited by 27 publications

(30 citation statements)

References 62 publications

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“…sites of the predominant localisation of this protein) of the SNpc dopaminergic neurons are located. However, such a late-onset depletion did not lead to any loss of SNpc dopaminergic neurons [12]. Taken together, results of our two studies strongly suggest that alpha-synuclein is required for efficient survival or maturation of dopaminergic neurons in the developing SNpc but is dispensable for survival of mature SNpc dopaminergic neurons.…”

Section: Resultssupporting

confidence: 55%

Reduced complement of dopaminergic neurons in the substantia nigra pars compacta of mice with a constitutive “low footprint” genetic knockout of alpha-synuclein

Goloborshcheva¹,

Chaprov²,

Teterina³

et al. 2020

Mol Brain

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Previous studies of the alpha-synuclein null mutant mice on the C57Bl6 genetic background have revealed reduced number of dopaminergic neurons in their substantia nigra pars compacta (SNpc). However, the presence in genomes of the studied mouse lines of additional genetic modifications that affect expression of genes located in a close proximity to the alpha-synuclein-encoding Snca gene makes these data open to various interpretations. To unambiguously demonstrate that the absence of alpha-synuclein is the primary cause of the observed deficit of dopaminergic neurons, we employed a recently produced constituent alpha-synuclein knockout mouse line B6(Cg)-Snca tm1.2Vlb /J. The only modification introduced to the genome of these mice is a substitution of the first coding exon and adjusted short intronic fragments of the Snca gene by a single loxP site. We compared the number of dopaminergic neurons in the SNpc of this line, previously studied B6(Cg)-Snca tm1Rosl /J line and wild type littermate mice. A similar decrease was observed in both knockout lines when compared with wild type mice. In a recently published study we revealed no loss of dopaminergic neurons following conditional inactivation of the Snca gene in neurons of adult mice. Taken together, these results strongly suggest that alpha-synuclein is required for efficient survival or maturation of dopaminergic neurons in the developing SNpc but is dispensable for survival of mature SNpc dopaminergic neurons.

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Section: Resultssupporting

confidence: 55%

Reduced complement of dopaminergic neurons in the substantia nigra pars compacta of mice with a constitutive “low footprint” genetic knockout of alpha-synuclein

Goloborshcheva¹,

Chaprov²,

Teterina³

et al. 2020

Mol Brain

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“…The copyright holder for this preprint this version posted November 20, 2020. ; https://doi.org/10.1101/2020.11.19.390419 doi: bioRxiv preprint 10 from the brain. Yet, removal of αSyn can cause functional changes to neuronal synapses in various in vivo experimental systems, particularly in the aged nervous system (Al-Wandi et al, 2010;Benskey et al, 2018;Collier et al, 2016;Gorbatyuk et al, 2010;Markopoulou et al, 2014;Ninkina et al, 2020;Robertson et al, 2004), and strategies targeting βSyn or γSyn to alter aggregation-prone pools of αSyn may be less detrimental.…”

Section: Discussionmentioning

confidence: 99%

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

Carnazza

Komer

Pineda

et al. 2020

Preprint

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SUMMARYα-Synuclein (αSyn), β-synuclein (βSyn), and γ-synuclein (γSyn) are abundantly expressed in the vertebrate nervous system. αSyn functions in neurotransmitter release via binding to and clustering synaptic vesicles and chaperoning of SNARE-complex assembly. The functions of βSyn and γSyn are unknown. Functional redundancy of the three synucleins and mutual compensation when one synuclein is deleted have been proposed, but with conflicting evidence. Here, we demonstrate that βSyn and γSyn have a reduced affinity towards membranes compared to αSyn, and that direct interaction of βSyn or γSyn with αSyn results in reduced membrane binding of αSyn. Our data suggest that all three synucleins affect synapse function, but only αSyn mediates the downstream function of vesicle clustering and SNARE-complex assembly, while βSyn and γSyn modulate the activity of αSyn through regulating its binding to synaptic vesicles.

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“…Fixation, processing, embedding, preparing of microtome sections and their immunostaining with antibody against TH (mouse monoclonal, clone TH-2 from Sigma, diluted 1:1000) were performed as in our previous studies [12,24]. Stereological counting of neurons was carried out as previously described for single and double synuclein KO mice [26,27].…”

Section: Methodsmentioning

confidence: 99%

β-synuclein promotes synaptic vesicle dopamine uptake and rescues dopaminergic neurons from MPTP-induced death

Ninkina¹,

Millership²,

Peters³

et al. 2020

Preprint

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Background. Previous studies demonstrated that dopaminergic neurons in the substantia nigra pars compacta (SNpc) of mice with null mutations for genes encoding α-synuclein and/or γ-synuclein are resistant to 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) toxicity. An original straightforward interpretation of these results was that these proteins are directly involved in the mechanism of MPTP-induced degeneration and this view has become commonly accepted. Here we provide evidence that a plausible alternative explanation of this resistance is not the absence of these synucleins per se but their substitution on the membrane of synaptic vesicles by the third member of the family, β-synuclein. Methods. An effect of sub-chronic MPTP regimen on dopaminergic neurons of SNpc was studied in mice lacking members of the synuclein family in all possible combinations. Dopamine uptake was assessed in synaptic vesicles isolated from synuclein null mutant mice. Protein composition of synaptic vesicles was studied by mass spectrometry. Results. Dopaminergic neurons of mice lacking β-synuclein singularly or in combination with the loss of other synucleins, were sensitive to the toxic effect of MPTP. Dopamine uptake by synaptic vesicles isolated from the striatum of triple α/β/γ-synuclein deficient mice was significantly reduced, while reintroduction of β-synuclein either in vivo or in vitro reversed this effect. Proteomic analysis of complexes formed on the surface of synuclein-free synaptic vesicles after addition of recombinant β-synuclein identified multiple integral constituents of these vesicles as well as typically cytosolic proteins, including key enzymes involved in dopamine synthesis, tyrosine hydroxylase (TH) and aromatic L-amino acid decarboxylase (AADC). Conclusions. Of the three members of the synuclein family, only β-synuclein can play a scaffolding role for the assembly of molecular complexes that potentiate the ability of synaptic vesicles to uptake and sequester dopamine and other structurally similar molecules, including 1-methyl-4-phenylpyridinium (MPP+), a toxic metabolite of MPTP. The increased presence and activity of β-synuclein at the synaptic vesicles, and not the absence of other synucleins per se, explains the decreased sensitivity to MPTP toxicity of SNpc dopaminergic neurons in mice lacking α-synuclein and/or γ-synuclein.

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Alterations in the nigrostriatal system following conditional inactivation of α-synuclein in neurons of adult and aging mice

Cited by 27 publications

References 62 publications

Reduced complement of dopaminergic neurons in the substantia nigra pars compacta of mice with a constitutive “low footprint” genetic knockout of alpha-synuclein

Reduced complement of dopaminergic neurons in the substantia nigra pars compacta of mice with a constitutive “low footprint” genetic knockout of alpha-synuclein

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

β-synuclein promotes synaptic vesicle dopamine uptake and rescues dopaminergic neurons from MPTP-induced death

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