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.
Highlights
Background aSynuclein (a-Syn) is a presynaptic, ubiquitously expressed protein in the brain, whose chief physiological function may be the regulation of synaptic levels of dopamine and other monoamines through modulation of the re-uptake function of monoamine transporters [1]
We found Tau hyperphosphorylated at Ser202, Ser262 and Ser396/ 404, which was accompanied by elevated levels of a-Syn and p-Glycogen Synthase Kinase-3b (GSK-3b)
Expression levels of a-Syn in different brain regions of the PDGF-a-Syn overexpressing mice We have previously [33] shown that a-Syn levels are significantly [p < 0.05] elevated [by 113% compared to litter-mate non-transgenic mice] in striata of PDGF-aSyn overexpressing mice and that such changes were accompanied by profound tauopathy and increased levels of p-GSK-3b, the kinase known to hyperphosphorylate Tau at distinct epitopes
Summary
Background aSynuclein (a-Syn) is a presynaptic, ubiquitously expressed protein in the brain, whose chief physiological function may be the regulation of synaptic levels of dopamine and other monoamines through modulation of the re-uptake function of monoamine transporters [1]. We have shown in the MPTP/MPP+ in vivo and in vitro models of PD, respectively, that increases in a-Syn can initiate and sustain p-Tau formation with hyperphosphorylation at Ser202, Ser262 and Ser396/404, which are the same epitopes that are hyperphosphorylated in AD and lead to pathological changes [29,30,31,32]. We found increases in levels of active GSK-3b [p-GSK-3b, hyperphosphorylated at Tyr216], a major kinase known to hyperphosphorylate Tau at the above mentioned sites. Blockade of this kinase with inhibitors prevent a-Syn-mediated p-Tau formation [29,31,32], thereby implicating p-GSK-3b in the mechanistic actions of a-Syn
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
