title: Age-dependent effects of A53T alpha-synuclein on behavior and dopaminergic function.
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.
authors.affiliation: Laboratory of Molecular Neurochemistry, Department of Biochemistry and Molecular & Cellular Biology, Georgetown University Medical Center, Washington, DC, USA.
authors.forename: Adam W
authors.initials: AW
authors.lastname: Oaks
authors.forename: Maya
authors.initials: M
authors.lastname: Frankfurt
authors.forename: David I
authors.initials: DI
authors.lastname: Finkelstein
authors.forename: Anita
authors.initials: A
authors.lastname: Sidhu
mesh_terms: D000367:Age Factors; D000818:Animals; D003342:Corpus Striatum / Q000378:metabolism* / Q000503:physiopathology; D004298:Dopamine / Q000378:metabolism*; D050483:Dopamine Plasma Membrane Transport Proteins / Q000235:genetics / Q000378:metabolism; D005786:Gene Expression Regulation; D006801:Humans; D051379:Mice; D008822:Mice, Transgenic; D009043:Motor Activity / Q000235:genetics; D009154:Mutation; D010300:Parkinson Disease / Q000235:genetics* / Q000378:metabolism / Q000503:physiopathology; D010766:Phosphorylation; D011328:Prions / Q000235:genetics; D011401:Promoter Regions, Genetic; D013378:Substantia Nigra / Q000378:metabolism* / Q000503:physiopathology; D009435:Synaptic Transmission; D051844:alpha-Synuclein / Q000235:genetics* / Q000378:metabolism; D051846:beta-Synuclein / Q000235:genetics / Q000378:metabolism; D051845:gamma-Synuclein / Q000235:genetics / Q000378:metabolism; D016875:tau Proteins / Q000235:genetics / Q000378:metabolism
chemical_list: D050483:Dopamine Plasma Membrane Transport Proteins; D011328:Prions; C497604:SNCA protein, human; D051844:alpha-Synuclein; D051846:beta-Synuclein; D051845:gamma-Synuclein; D016875:tau Proteins; D004298:Dopamine
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