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Age-Dependent Effects of A53T Alpha-Synuclein on Behavior and Dopaminergic Function

Expression of A53T mutant human alpha-synuclein under the mouse prion promoter is among the most successful transgenic models of Parkinson's disease. Accumulation of A53T alpha-synuclein causes adult mice to develop severe motor impairment resulting in early death at 8–12 months of age. In youn...

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Autores principales: Oaks, Adam W., Frankfurt, Maya, Finkelstein, David I., Sidhu, Anita
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Public Library of Science 2013
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3613356/
https://www.ncbi.nlm.nih.gov/pubmed/23560093
http://dx.doi.org/10.1371/journal.pone.0060378
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author Oaks, Adam W.
Frankfurt, Maya
Finkelstein, David I.
Sidhu, Anita
author_facet Oaks, Adam W.
Frankfurt, Maya
Finkelstein, David I.
Sidhu, Anita
author_sort Oaks, Adam W.
collection PubMed
description Expression of A53T mutant human alpha-synuclein under the mouse prion promoter is among the most successful transgenic models of Parkinson's disease. Accumulation of A53T alpha-synuclein causes adult mice to develop severe motor impairment resulting in early death at 8–12 months of age. In younger, pre-symptomatic animals, altered motor activity and anxiety-like behaviors have also been reported. These behavioral changes, which precede severe neuropathology, may stem from non-pathological functions of alpha-synuclein, including modulation of monoamine neurotransmission. Our analysis over the adult life-span of motor activity, anxiety-like, and depressive-like behaviors identifies perturbations both before and after the onset of disease. Young A53T mice had increased distribution of the dopamine transporter (DAT) to the membrane that was associated with increased striatal re-uptake function. DAT function decreased with aging, and was associated with neurochemical alterations that included increased expression of beta-synuclein and gamma synuclein. Prior to normalization of dopamine uptake, transient activation of Tau kinases and hyperphosphorylation of Tau in the striatum were also observed. Aged A53T mice had reduced neuron counts in the substantia nigra pars compacta, yet striatal medium spiny neuron dendritic spine density was largely maintained. These findings highlight the involvement of the synuclein family of proteins and phosphorylation of Tau in the response to dopaminergic dysfunction of the nigrostriatal pathway.
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spelling pubmed-36133562013-04-04 Age-Dependent Effects of A53T Alpha-Synuclein on Behavior and Dopaminergic Function Oaks, Adam W. Frankfurt, Maya Finkelstein, David I. Sidhu, Anita PLoS One Research Article Expression of A53T mutant human alpha-synuclein under the mouse prion promoter is among the most successful transgenic models of Parkinson's disease. Accumulation of A53T alpha-synuclein causes adult mice to develop severe motor impairment resulting in early death at 8–12 months of age. In younger, pre-symptomatic animals, altered motor activity and anxiety-like behaviors have also been reported. These behavioral changes, which precede severe neuropathology, may stem from non-pathological functions of alpha-synuclein, including modulation of monoamine neurotransmission. Our analysis over the adult life-span of motor activity, anxiety-like, and depressive-like behaviors identifies perturbations both before and after the onset of disease. Young A53T mice had increased distribution of the dopamine transporter (DAT) to the membrane that was associated with increased striatal re-uptake function. DAT function decreased with aging, and was associated with neurochemical alterations that included increased expression of beta-synuclein and gamma synuclein. Prior to normalization of dopamine uptake, transient activation of Tau kinases and hyperphosphorylation of Tau in the striatum were also observed. Aged A53T mice had reduced neuron counts in the substantia nigra pars compacta, yet striatal medium spiny neuron dendritic spine density was largely maintained. These findings highlight the involvement of the synuclein family of proteins and phosphorylation of Tau in the response to dopaminergic dysfunction of the nigrostriatal pathway. Public Library of Science 2013-04-01 /pmc/articles/PMC3613356/ /pubmed/23560093 http://dx.doi.org/10.1371/journal.pone.0060378 Text en © 2013 Oaks et al http://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are properly credited.
spellingShingle Research Article
Oaks, Adam W.
Frankfurt, Maya
Finkelstein, David I.
Sidhu, Anita
Age-Dependent Effects of A53T Alpha-Synuclein on Behavior and Dopaminergic Function
title Age-Dependent Effects of A53T Alpha-Synuclein on Behavior and Dopaminergic Function
title_full Age-Dependent Effects of A53T Alpha-Synuclein on Behavior and Dopaminergic Function
title_fullStr Age-Dependent Effects of A53T Alpha-Synuclein on Behavior and Dopaminergic Function
title_full_unstemmed Age-Dependent Effects of A53T Alpha-Synuclein on Behavior and Dopaminergic Function
title_short Age-Dependent Effects of A53T Alpha-Synuclein on Behavior and Dopaminergic Function
title_sort age-dependent effects of a53t alpha-synuclein on behavior and dopaminergic function
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3613356/
https://www.ncbi.nlm.nih.gov/pubmed/23560093
http://dx.doi.org/10.1371/journal.pone.0060378
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