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Alpha-synuclein is involved in manganese-induced spatial memory and synaptic plasticity impairments via TrkB/Akt/Fyn-mediated phosphorylation of NMDA receptors.

ABSTRACT: Manganese (Mn) overexposure produces long-term cognitive deficits and reduces brain-derived neurotrophic factor (BDNF) in the hippocampus. However, it remains elusive whether Mn-dependent enhanced alpha-synuclein (?-Syn) expression, suggesting a multifaceted mode of neuronal toxicities, accounts for interference with BDNF/TrkB signaling. In this study, we used C57BL/6J WT and ?-Syn knockout (KO) mice to establish a model of manganism and found that Mn-induced impairments in spatial memory and synaptic plasticity were related to the ?-Syn protein. In addition, consistent with the long-term potentiation (LTP) impairments that were observed, ?-Syn KO relieved Mn-induced degradation of PSD95, phosphorylated CaMKII?, and downregulated SynGAP protein levels. We transfected HT22 cells with lentivirus (LV)-?-Syn shRNA, followed by BDNF and Mn stimulation. In vitro experiments indicated that ?-Syn selectively interacted with TrkB receptors and inhibited BDNF/TrkB signaling, leading to phosphorylation and downregulation of GluN2B. The binding of ?-Syn to TrkB and Fyn-mediated phosphorylation of GluN2B were negatively regulated by BDNF. Together, these findings indicate that Mn-dependent enhanced ?-Syn expression contributes to further exacerbate BDNF protein-level reduction and to inhibit TrkB/Akt/Fyn signaling, thereby disturbing Fyn-mediated phosphorylation of the NMDA receptor GluN2B subunit at tyrosine. In KO ?-Syn mice treated with Mn, spatial memory and LTP impairments were less pronounced than in WT mice. However, the same robust neuronal death was observed as a result of Mn-induced neurotoxicity.

SUBMITTER: Ma Z

PROVIDER: S-EPMC7545185 | biostudies-literature | 2020 Oct

REPOSITORIES: biostudies-literature

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Alpha-synuclein is involved in manganese-induced spatial memory and synaptic plasticity impairments via TrkB/Akt/Fyn-mediated phosphorylation of NMDA receptors.

Ma Zhuo Z Liu Kuan K Li Xin-Ru XR Wang Can C Liu Chang C Yan Dong-Ying DY Deng Yu Y Liu Wei W Xu Bin B

Cell death & disease 20201008 10

Manganese (Mn) overexposure produces long-term cognitive deficits and reduces brain-derived neurotrophic factor (BDNF) in the hippocampus. However, it remains elusive whether Mn-dependent enhanced alpha-synuclein (α-Syn) expression, suggesting a multifaceted mode of neuronal toxicities, accounts for interference with BDNF/TrkB signaling. In this study, we used C57BL/6J WT and α-Syn knockout (KO) mice to establish a model of manganism and found that Mn-induced impairments in spatial memory and sy ...[more]

PMID: 33033239

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Project description:Parkinsonâs disease (PD), the second most frequent neurodegenerative disorder at old age, can be caused by elevated expression, or the A53T mutation, of the presynaptic protein alpha-synuclein (SNCA). PD is characterized pathologically by the preferential vulnerability of the dopaminergic nigrostriatal projection neurons. Here, we used two mouse lines overexpressing human A53T-SNCA around ages 6 and 18 months and studied striatal dysfunction in the absence of neurodegeneration to understand early disease mechanisms. High pressure liquid chromatography analysis of striatal neurotransmitter content demonstrated that dopamine (DA) levels correlated directly with the level of expression of SNCA, an observation also observed in SNCA deficient mice. In the striatum of aged A53TSNCA overexpressing mice, where DA levels were elevated, a paradoxical upregulation of dopamine receptors DRD1A and DRD2 was detected by immunoblots and autoradiography, findings compatible with the notion of abnormal vesicle release. Extensive transcriptome studies via microarrays and quantitative real-time RT-PCR validation of altered Homer1, Cb1, Atf2 and Pde7b transcript levels indicated a progressive reduction in the postsynaptic DA response. As functional consequences, long term depression was absent in corticostriatal slices from aged transgenic mice and an insidious decrease of spontaneous locomotor activity of these animals was found in open field tests. Taken together, the dysfunctional neurotransmission and decreased synaptic plasticity seen in the A53T-SNCA overexpressing mice reflects early functional changes within the basal ganglia resulting from synucleinopathy prior to frank neurodegeneration. Thus, preclinical stages of PD may be modeled in this mouse. Parkinsonâs disease (PD), the second most frequent neurodegenerative disorder at old age, can be caused by elevated expression, or the A53T mutation, of the presynaptic protein alpha-synuclein (SNCA). PD is characterized pathologically by the preferential vulnerability of the dopaminergic nigrostriatal projection neurons. Here, we used two mouse lines overexpressing human A53T-SNCA around ages 6 and 18 months and studied striatal dysfunction in the absence of neurodegeneration to understand early disease mechanisms. High pressure liquid chromatography analysis of striatal neurotransmitter content demonstrated that dopamine (DA) levels correlated directly with the level of expression of SNCA, an observation also observed in SNCA deficient mice. In the striatum of aged A53TSNCA overexpressing mice, where DA levels were elevated, a paradoxical upregulation of dopamine receptors DRD1A and DRD2 was detected by immunoblots and autoradiography, findings compatible with the notion of abnormal vesicle release. Extensive transcriptome studies via microarrays and quantitative real-time RT-PCR validation of altered Homer1, Cb1, Atf2 and Pde7b transcript levels indicated a progressive reduction in the postsynaptic DA response. As functional consequences, long term depression was absent in corticostriatal slices from aged transgenic mice and an insidious decrease of spontaneous locomotor activity of these animals was found in open field tests. Taken together, the dysfunctional neurotransmission and decreased synaptic plasticity seen in the A53T-SNCA overexpressing mice reflects early functional changes within the basal ganglia resulting from synucleinopathy prior to frank neurodegeneration. Thus, preclinical stages of PD may be modeled in this mouse. Tissue was dissected from the brain of 6 months old (2 WT / 2 TgA / 2 TgB striata, 2 WT / 2 TgA / 2 TgB brainstems/midbrains, 2 WT / 2 TgA / 2 TgB cerebella) and of 18+ months old mice (4 WT / 2 TgA / 2 TgB striata, 6 WT / 4 TgA / 3 TgB brainstems/midbrains, 6 WT / 5 TgA / 4 TgB cerebella). Tissues from individual, particularly old mice up to 28 months age were included here to strengthen the definition of progression markers reflecting old age.

Dataset Information

Alpha-synuclein is involved in manganese-induced spatial memory and synaptic plasticity impairments via TrkB/Akt/Fyn-mediated phosphorylation of NMDA receptors.

Publications

Alpha-synuclein is involved in manganese-induced spatial memory and synaptic plasticity impairments via TrkB/Akt/Fyn-mediated phosphorylation of NMDA receptors.

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