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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Available from: David I Finkelstein, Oct 05, 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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    ABSTRACT: The groundbreaking discovery of mutations in the SNCA gene in a rare familial form of Parkinson's disease (PD) has revolutionized our basic understanding of the etiology of PD and other related disorders. Genome-wide Association Studies has demonstrated a wide array of single-nucleotide polymorphisms associated with the increasing risk of developing the more common type, sporadic PD, further corroborating the genetic etiology of PD. Among them, SNCA is a gene responsible for encoding α-synuclein, a protein found to be the major component of Lewy body and Lewy neurite, both of these components are the pathognomonic hallmarks of PD. Thus, it has been postulated that this gene plays specific roles in pathogenesis of PD. Here, we summarize the basic biological characteristics of the wild type of the protein (wt-α-synuclein) as well as genetic and epigenetic features of its encoding gene (SNCA) in PD. Based on these characteristics, SNCA may be involved in PD pathogenesis in at least 2 ways: wt-α-synuclein overexpression and its mutation types via different mechanisms. Associations between SNCA mutations and other Lewy body disorders, such as dementia with Lewy bodies and multiple system atrophy, are also mentioned. Finally, it is necessary to explore the influences which SNCA exerts on clinical and neuropathological phenotypes by promoting the transfer of scientific research into practice, such as clinical evaluation, diagnosis, and treatment of the disease. We believe it is promising to target SNCA for developing novel therapeutic strategies for parkinsonism. Copyright © 2014 Elsevier Inc. All rights reserved.
    Neurobiology of Aging 12/2014; 36(3). DOI:10.1016/j.neurobiolaging.2014.10.042 · 5.01 Impact Factor
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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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    ABSTRACT: Parkinson disease (PD; MIM 168600) is the second most common progressive neurodegenerative disorder characterized by a variety of motor and non-motor features. To date, at least 20 loci and 15 disease-causing genes for parkinsonism have been identified. Among them, the α-synuclein (SNCA) gene was associated with PARK1/PARK4. Point mutations, duplications and triplications in the SNCA gene cause a rare dominant form of PD in familial and sporadic PD cases. The α-synuclein protein, a member of the synuclein family, is abundantly expressed in the brain. The protein is the major component of Lewy bodies and Lewy neurites in dopaminergic neurons in PD. Further understanding of its role in the pathogenesis of PD through various genetic techniques and animal models will likely provide new insights into our understanding, therapy and prevention of PD.
    Ageing research reviews 04/2014; 15(1). DOI:10.1016/j.arr.2014.04.002 · 4.94 Impact Factor
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    • "Among proposed functions is a role for Syn proteins as regulators of membrane protein trafficking. In our most recent work, we have continued our examination of the involvement of the 3 family members α-Syn, β-Syn (β-Syn), and gamma-Syn (γ-Syn) in regulated trafficking of the dopamine transporter (DAT) in both cellular and animal models of Syn protein overexpression.1,2 Trafficking of DAT and other monoamine transporters of norepinephrine (NET) and serotonin (SERT) has been linked to the Syn proteins for over a decade.3 "
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    ABSTRACT: More than 2 decades of work have yet to conclusively determine the physiological role of the synuclein proteins, even though these abundant brain constituents are participants in a broad array of cellular processes. Among proposed physiological roles is a functional interaction between the synuclein proteins and monoamine transporters contributing to transporter trafficking through direct protein-protein interactions. Recent work shows that an antagonistic effect of the synuclein proteins on the secretory functions of the endoplasmic reticulum and the Golgi apparatus appears to simultaneously influence trafficking of the dopamine transporter and other membrane proteins. Here, we highlight these new findings in view of the broader literature identifying the role of synucleins in protein trafficking and suggest emerging themes for ongoing and future work in the field of synuclein biology.
    Communicative & integrative biology 11/2013; 6(6):e26794. DOI:10.4161/cib.26794
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