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Cytoskeleton as a Target of Quinolinic Acid Neurotoxicity: Insight from Animal Models

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Abstract

Cytoskeletal proteins are increasingly recognized as having important roles as a target of the action of different neurotoxins. In the last years, several works of our group have shown that quinolinic acid (QUIN) was able to disrupt the homeostasis of the cytoskeleton of neural cells and this was associated with cell dysfunction and neurodegeneration. QUIN is an excitotoxic metabolite of tryptophan metabolism and its accumulation is associated with several neurodegenerative diseases. In the present review, we provide a comprehensive view of the actions of QUIN upstream of glutamate receptors, eliciting kinase/phosphatase signaling cascades that disrupt the homeostasis of the phosphorylation system associated with intermediate filament proteins of astrocytes and neurons. We emphasize the critical role of calcium in these actions and the evidence that misregulated cytoskeleton takes part of the cell response to the injury resulting in neurodegeneration in different brain regions, disrupted cell signaling in acute tissue slices, and disorganized cytoskeleton with altered cell morphology in primary cultures. We also discuss the interplay among misregulated cytoskeleton, oxidative stress, and cell-cell contact through gap junctions mediating the quinolinic acid injury in rat brain. The increasing amount of cross talks identified between cytoskeletal proteins and cellular signaling cascades reinforces the exciting possibility that cytoskeleton could be a new target in the neurotoxicity of QUIN and further studies will be necessary to develop strategies to protect the cytoskeleton and counteracts the cytotoxicity of this metabolite.

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  1. Departamento de Bioquímica, Instituto de Ciências Básicas da Saúde, Universidade Federal do Rio Grande do Sul, Rua Ramiro Barcelos 2600 Anexo, Porto Alegre, RS, 90035-003, Brazil

    Paula Pierozan & Regina Pessoa-Pureur

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Correspondence to Regina Pessoa-Pureur.

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This work was supported by grants of Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq) [grant number 303913/2013–4] and Fundação de Amparo à Pesquisa do Estado do Rio Grande do Sul (FAPERGS) [grant number 11/0897–0].

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Pierozan, P., Pessoa-Pureur, R. Cytoskeleton as a Target of Quinolinic Acid Neurotoxicity: Insight from Animal Models. Mol Neurobiol 55, 4362–4372 (2018). https://doi.org/10.1007/s12035-017-0654-8

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