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

Laboratory of Molecular Neurochemistry, Department of Biochemistry and Molecular & Cellular Biology, Georgetown University Medical Center, Washington, D.C., United States of America.
PLoS ONE (Impact Factor: 3.23). 04/2013; 8(4):e60378. DOI: 10.1371/journal.pone.0060378
Source: PubMed

ABSTRACT 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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Available from: David I Finkelstein, Aug 27, 2015
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    • "iplication mutations having temporal lobe vacuolation in addition to LB pathology ( Houlden and Singleton , 2012 ) . Furthermore , more neuropathological fea - tures have been demonstrated in subsequent researches with hu - man and animal models carrying SNCA single mutations ( Cannon et al . , 2013 ; Kiely et al . , 2013 ; Lesage et al . , 2013 ; Oaks et al . , 2013 ; Seidel et al . , 2010 ; Taylor et al . , 2014 ) . ( Table 2 ) These neuro - pathological characteristics may to some extent help us to differ - entiate the 2 types of PD . 6 . 2 . Potential values of SNCA in clinical diagnosis of PD a - Synuclein is ubiquitously expressed at a level accounting for 0 . 5%e1% of total intra - neuronal p"
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