Age-Dependent Effects of A53T Alpha-Synuclein on Behavior and Dopaminergic Function
AuthorOaks, AW; Frankfurt, M; Finkelstein, DI; Sidhu, A
Source TitlePLoS One
PublisherPUBLIC LIBRARY SCIENCE
University of Melbourne Author/sFinkelstein, David
AffiliationCentre For Neuroscience Research
Document TypeJournal Article
CitationsOaks, A. W., Frankfurt, M., Finkelstein, D. I. & Sidhu, A. (2013). Age-Dependent Effects of A53T Alpha-Synuclein on Behavior and Dopaminergic Function. PLOS ONE, 8 (4), https://doi.org/10.1371/journal.pone.0060378.
Access StatusAccess this item via the Open Access location
Open Access at PMChttp://www.ncbi.nlm.nih.gov/pmc/articles/PMC3613356
C1 - Journal Articles Refereed
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.
KeywordsNeurology and Neuromuscular Diseases; Neurodegenerative Disorders Related to Ageing
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