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


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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    • "-Synuclein has been proposed to regulate homeostasis of monoamines in synapses, via interaction with the serotonin transporter [165]. It binds to and regulates the targeting and the activity of the dopamine transporter DAT [166] [167] [200], although its mode of action remains controversial [201] [202] [203]. -Synuclein inhibits dopamine synthesis by inhibiting the expression and activity of tyrosine hydroxylase [154, 168–170, 204], likely via reducing the phosphorylation state of tyrosine hydroxylase and stabilizing dephosphorylated inactive tyrosine hydroxylase [168, 205–207]. "
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    ABSTRACT: α-Synuclein is an abundant neuronal protein which localizes predominantly to presynaptic terminals, and is strongly linked genetically and pathologically to Parkinson's disease and other neurodegenerative diseases. While the accumulation of α-synuclein in the form of misfolded oligomers and large aggregates defines multiple neurodegenerative diseases called "synucleinopathies", its cellular function has remained largely unclear, and is the subject of intense investigation. In this review, I focus on the structural characteristics of α-synuclein, its cellular and subcellular localization, and discuss how this relates to its function in neurons, in particular at the neuronal synapse.
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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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    Full-text · Article · Dec 2014 · Neurobiology of Aging
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    • "Mice expressing p.A53T hSNCA by a neuron-specific Thy1 promoter had progressive motor impairment, reduced anxiety and potential sleep disturbances, accompanied with decreases in the DA transporter and increases in serotonin and DA levels, providing additional phenotypes to previously generated PD model (Rothman et al., 2013). Mouse PrP-induced p.A53T hSNCA140 transgenic mice showed age-dependent motor impairment, behavioral perturbations , altered neurochemical function, and development of synucleinopathy and tauopathy, indicating the involvement of synuclein and tau in progression of PD (Oaks et al., 2013). In addition to the normal presynaptic localization, Thy1-induced transgenic WT and p.A30P hSNCA140 abnormally accumulated in neuronal cell bodies and neurites throughout the mouse brain, indicating that mutant p.A30P ␣-synuclein does not fail to be transported to synapses, but its transgenic overexpression apparently leads to abnormal cellular accumulations (Kahle et al., 2000). "
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