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.

Alpha-synuclein and tau: teammates in neurodegeneration?

“…Kaul and colleagues correlated phospho-tau occurrence with the activation of ERK and JNK but not of GSK3β and p38MAPK kinases, whereas Haggerty and colleagues noted a match between the presence of phospho-tau and phospho-GSK3β. Similarly, in the prion promoter driven A53T αsyn mice, as well as in patients harboring the A53T mutation, hyperphosphorylated and non-soluble tau accumulated in the striatum and was correlated with increased levels of phospho-GSK3β [105, 106]. In contrast, in a Thy-1 promoter driven A30P αsyn overexpressing transgenic mouse line, hyperphosphorylated and non-soluble tau accumulated in the brainstem in correlation with increased phospho-JNK level [107].…”

“…However GSK3β is not the only kinase that links αsyn with hyperphosphorylated tau. Indeed, activation of ERK and JNK, that also phosphorylate tau at S396 and S404 residues, correlate with the presence of phospho-tau in αsyn overexpressing transgenic mouse models [102, 106, 107]. In addition, tau phosphorylation at S262 and S356 residues by PKA is exacerbated by αsyn in vitro [127].…”

GSK-3β dysregulation contributes to parkinson’s-like pathophysiology with associated region-specific phosphorylation and accumulation of tau and α-synuclein

“…IHC analysis of mouse brain coronal sections was performed as previously described. 19,65 See supplementary material and methods for further details.…”

Olfactory Discrimination Deficits in A53T Alpha-Synuclein Transgenic Mice at 3 Months

“…Presently, neurogenesis was proposed to connected with olfactory discrimination [7]. Adult neurogenesis, the generation of new neurons within two areas in the adult brain, One is the subgranular zone of the hippocampus, the other is the subventricular zone, a structure known to be critical for olfactory discrimination [8,9,10,11,12], Lateral ventricle ependymal lower (SVZ) of newborn neurons in the rostral migration stream to the olfactory bulb, is very important to maintain normal sense of smell.…”

“…A multitude of literatures showed that Parkinson's early olfactory are inhibition [7,8,9], moreover, few people do olfactory discrimination with C57BL/6 mice. Therefore we use this PD model to investigate the performance of olfactory discrimination in the bedding test and fine odor discrimination task as well as the correlations of olfactory with other behaviors.…”