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

Adam W Oaks,David I Finkelstein,Anita Sidhu,Maya Frankfurt

doi:10.1371/journal.pone.0060378

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.

Highlights

Not diagnosed clinically until the onset of motor impairment, Parkinson’s disease (PD) is frequently associated with non-motor symptoms, including autonomic dysfunction, sleep abnormalities, and neuropsychiatric disorders [1]
To assess locomotor activity and motor performance, homozygous A53T mice were compared to wild-type controls (WT) mice at 2, 4, 8, and 12 months on several behavior tests including the open field test (OFT), elevated plus maze (EPM), rotarod, and wire hang test (WHT)
A53T mice showed significantly reduced locomotor activity compared to WT, as quantified by line breaks on the OFT (Fig. S1A) and distance traveled on both the OFT (Fig. 1A) and the elevated plus-maze (EPM) (Fig. S1B)

Summary

Introduction

Not diagnosed clinically until the onset of motor impairment, Parkinson’s disease (PD) is frequently associated with non-motor symptoms, including autonomic dysfunction, sleep abnormalities, and neuropsychiatric disorders [1]. The A53T a-Syn mouse model successfully recapitulates many important features of synucleinopathy, including age-dependent neurodegeneration [3]. As pre-clinical a-Syn models of PD that may be used to test new therapies, it is critical to determine whether the neuropsychiatric phenotypes of a-Syn transgenic mice accurately reflect the human disorder. Both the dopamine transporter (DAT) and the norepinephrine transporter (NET), which are subject to modulation by the Syn proteins in cellular trafficking models [13], are linked to these neuropsychiatric symptoms, and are important drug targets in the treatment of depression, anxiety, and related mood disorders [14]. Recent work in mouse models of synucleinopathy has begun to examine non-motor aspects, including behaviors related to the neuropsychiatric symptoms of PD, but a comprehensive analysis remains incomplete (see detailed reviews in [15,16])

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Results

Conclusion