Region-specific tauopathy and synucleinopathy in brain of the alpha-synuclein overexpressing mouse model of Parkinson's disease

Abstract

Backgroundα-synuclein [α-Syn]-mediated activation of GSK-3β leading to increases in hyperphosphorylated Tau has been shown by us to occur in striata of Parkinson's diseased [PD] patients and in animal models of PD. In Alzheimer's disease, tauopathy exists in several brain regions; however, the pattern of distribution of tauopathy in other brain regions of PD or in animal models of PD is not known. The current studies were undertaken to analyze the distribution of tauopathy in different brain regions in a widely used mouse model of PD, the α-Syn overexpressing mouse.ResultsHigh levels of α-Syn levels were seen in the brain stem, with a much smaller increase in the frontal cortex; neither cerebellum nor hippocampus showed any overexpression of α-Syn. Elevated levels of p-Tau, hyperphosphorylated at Ser202, Ser262 and Ser396/404, were seen in brain stem, with lower levels seen in hippocampus. In both frontal cortex and cerebellum, increases were seen only in p-Ser396/404 Tau, but not in p-Ser202 and p-Ser262. p-GSK-3β levels were not elevated in any of the brain regions, although total GSK-3β was elevated in brain stem. p-p38MAPK levels were unchanged in all brain regions examined, while p-ERK levels were elevated in brain stem, hippocampus and cerebellum, but not the frontal cortex. p-JNK levels were increased in brain stem and cerebellum but not in the frontal cortex or hippocampus. Elevated levels of free tubulin, indicating microtubule destabilization, were seen only in the brain stem.ConclusionOur combined data suggest that in this animal model of PD, tauopathy, along with microtubule destabilization, exists primarily in the brain stem and striatum, which are also the two major brain regions known to express high levels of α-Syn and undergo the highest levels of degeneration in human PD. Thus, tauopathy in PD may have a very restricted pattern of distribution.

Pathological Interface Between Oligomeric Alpha-Synuclein and Tau in Synucleinopathies

“…It has been described that in an α-synuclein overexpressing PD mouse model, tau pathology developed in some particular regions of the brain. Tau pathology progressed hand-inhand with the development of synuclein pathology in this mouse model (68). Thus, the interaction between tau and α-synuclein is gaining increased attention for its possible pathogenic role in synucleinopathies.…”

Compromised MAPK signaling in human diseases: an update

“…The restricted distribution of neurofibrillary tangles in the brain of an α-synuclein-overexpressing mouse model of PD was found to correlate with increased levels of phosphorylated (activated) forms of JNK and ERK, but not with the level of phosphorylated p38 MAPK (Kaul et al 2011). In contrast, the activity of ERK1/2, but not that of JNK or p38 MAPK, is reduced in the substantia nigra of Smad3-deficient mice, which also manifest dopaminergic neuronal degeneration (Tapia-Gonzalez et al 2011).…”

The role of α-synuclein in neurodegeneration — An update

“…DA D1 receptor activation induces tau phosphorylation via cyclin-dependent kinase 5 (cdk5) and GSK-3β signalling pathways [586]. Thus, tauopathy in PD may have a restricted pattern of distribution [578], which differs from its generalized affection in AD.…”

“…Cellular, various tg and other experimental PD models provided new insight in the hyperphosphorylation of tau [566,569,[576][577][578][579][580]. They suggest that oxidatively modified AS is degraded by the proteasome and plays a pro-aggretatory role for tau [581], and that AS is an in vivo regulator for tau phosphorylation at Ser 262 leading to deposition of both proteins [582].…”