-Synuclein contributes to GSK-3 -catalyzed Tau phosphorylation in Parkinson's disease models (original) (raw)
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Cell death and differentiation, 2014
Aberrant posttranslational modifications (PTMs) of proteins, namely phosphorylation, induce abnormalities in the biological properties of recipient proteins, underlying neurological diseases including Parkinson's disease (PD). Genome-wide studies link genes encoding α-synuclein (α-Syn) and Tau as two of the most important in the genesis of PD. Although several kinases are known to phosphorylate α-Syn and Tau, we focused our analysis on GSK-3β because of its accepted role in phosphorylating Tau and to increasing evidence supporting a strong biophysical relationship between α-Syn and Tau in PD. Therefore, we investigated transgenic mice, which express a point mutant (S9A) of human GSK-3β. GSK-3β-S9A is capable of activation through endogenous natural signaling events, yet is unable to become inactivated through phosphorylation at serine-9. We used behavioral, biochemical, and in vitro analysis to assess the contributions of GSK-3β to both α-Syn and Tau phosphorylation. Behavioral ...
Hyperphosphorylated Tau in an α-synuclein-overexpressing transgenic model of Parkinson’s disease
European Journal of Neuroscience, 2011
Although clinically distinct diseases, tauopathies and synucleinopathies share common genesis and mechanisms, leading to overlapping degenerative changes within neurons. In human postmortem striatum of Parkinson's disease [PD] and PD with dementia, we have recently described elevated levels of tauopathy, indexed as increased hyperphosphorylated Tau [p-Tau].
Mechanisms in dominant parkinsonism: The toxic triangle of LRRK2, α-synuclein, and tau
Bioessays, 2010
Parkinson's disease (PD) is generally sporadic but a number of genetic diseases have parkinsonism as a clinical feature. Two dominant genes, α-synuclein (SNCA) and leucine-rich repeat kinase 2 (LRRK2), are important for understanding inherited and sporadic PD. SNCA is a major component of pathologic inclusions termed Lewy bodies found in PD. LRRK2 is found in a significant proportion of PD cases. These two proteins may be linked as most LRRK2 PD cases have SNCA-positive Lewy bodies. Mutations in both proteins are associated with toxic effects in model systems although mechanisms are unclear. LRRK2 is an intracellular signaling protein possessing both GTPase and kinase activities that may contribute to pathogenicity. A third protein, tau, is implicated as a risk factor for PD. We discuss the potential relationship between these genes and suggest a model for PD pathogenesis where LRRK2 is upstream of pathogenic effects through SNCA, tau, or both proteins.
Tauopathic Changes in the Striatum of A53T α-Synuclein Mutant Mouse Model of Parkinson's Disease
PLoS ONE, 2011
Tauopathic pathways lead to degenerative changes in Alzheimer's disease and there is evidence that they are also involved in the neurodegenerative pathology of Parkinson's disease [PD]. We have examined tauopathic changes in striatum of the asynuclein (a-Syn) A53T mutant mouse. Elevated levels of a-Syn were observed in striatum of the adult A53T a-Syn mice. This was accompanied by increases in hyperphosphorylated Tau [p-Tau], phosphorylated at Ser202, Ser262 and Ser396/404, which are the same toxic sites also seen in Alzheimer's disease. There was an increase in active p-GSK-3b, hyperphosphorylated at Tyr216, a major and primary kinase known to phosphorylate Tau at multiple sites. The sites of hyperphosphorylation of Tau in the A53T mutant mice were similar to those seen in post-mortem striata from PD patients, attesting to their pathophysiological relevance. Increases in p-Tau were not due to alterations on protein phosphatases in either A53T mice or in human PD, suggesting lack of involvement of these proteins in tauopathy. Extraction of striata with Triton X-100 showed large increases in oligomeric forms of a-Syn suggesting that a-Syn had formed aggregates the mutant mice. In addition, increased levels of p-GSK-3b and pSer396/404 were also found associated with aggregated a-Syn. Differential solubilization to measure protein binding to cytoskeletal proteins demonstrated that p-Tau in the A53T mutant mouse were unbound to cytoskeletal proteins, consistent with dissociation of p-Tau from the microtubules upon hyperphosphorylation. Interestingly, a-Syn remained tightly bound to the cytoskeleton, while p-GSK-3b was seen in the cytoskeleton-free fractions. Immunohistochemical studies showed that a-Syn, pSer396/404 Tau and p-GSK-3b co-localized with one another and was aggregated and accumulated into large inclusion bodies, leading to cell death of Substantia nigral neurons. Together, these data demonstrate an elevated state of tauopathy in striata of the A53T a-Syn mutant mice, suggesting that tauopathy is a common feature of synucleinopathies. Citation: Wills J, Credle J, Haggerty T, Lee J-H, Oaks AW, et al. (2011) Tauopathic Changes in the Striatum of A53T a-Synuclein Mutant Mouse Model of Parkinson's Disease. PLoS ONE 6(3): e17953.
Journal of Biological Chemistry, 2011
In Parkinson disease (PD) brain, a progressive loss of dopaminergic neurons leads to dopamine depletion in the striatum and reduced motor function. Lewy bodies, the characteristic neuropathological lesions found in the brain of PD patients, are composed mainly of ␣-synuclein protein. Three point mutations in the ␣-synuclein gene are associated with familial PD. In addition, genome-wide association studies indicate that ␣-synuclein and Tau protein synergistically increase disease susceptibility in the human population. To determine the mechanism by which ␣-synuclein and Tau act together, we have used PD-causing neurotoxin MPTP and pathogenic ␣-synuclein mutants A30P, E46K, and A53T as models. We found that exposure of human neuroblastoma M17 cells to MPTP enhances the intracellular ␣-synuclein protein level, stimulates Tau protein phosphorylation at Ser 262 , and induces apoptosis. In mouse brain, ablation of ␣-synuclein function significantly suppresses Tau phosphorylation at Ser 262. In vitro, ␣-synuclein binds to phosphorylated Ser 214 of Tau and stimulates PKA-catalyzed Tau phosphorylation at Ser 262. PDassociated ␣-synuclein mutations increase ␣-synuclein binding to Tau and stimulate Tau phosphorylation at Ser 262. In HEK-293 cells, ␣-synuclein and its all PD-associated mutants destabilize the microtubule cytoskeleton in a similar extent. In contrast, when co-expressed with Tau, these PD-associated mutants destabilize microtubules with significantly higher potency than WT. Our results demonstrate that ␣-synuclein is an in vivo regulator of Tau protein phosphorylation at Ser 262 and suggest that PD-associated risk factors such as environmental toxins and ␣-synuclein mutations promote Tau phosphorylation at Ser 262 , causing microtubule instability, which leads to loss of dopaminergic neurons in PD brain.
Alpha-Synuclein Induces Hyperphosphorylation of Au in the Mptp Model of Parkinsonism
The FASEB Journal, 2006
dysregulation, including Alzheimer's disease (AD) and other tauopathies, also show ␣-synuclein (␣-Syn) pathology, a protein associated with Parkinson's disease (PD) pathology. Here we show that treatment of primary mesencephalic neurons (48 h) or subchronic treatment of wild-type (WT) mice with the Parkinsonism-inducing neurotoxin MPP ؉ /MPTP, results in selective dose-dependent hyperphosphorylation of Tau at Ser396/404 (PHF-1-reactive Tau, p-Tau), with no changes in pSer202 but with nonspecific increases in pSer262 levels. The presence of ␣-Syn was absolutely mandatory to observe MPP ؉ /MPTP-induced increases in p-Tau levels, since no alterations in p-Tau were seen in transfected cells not expressing ␣-Syn or in ␣-Syn؊/؊ mice. MPP ؉ /MPTP also induced a significant accumulation of ␣-Syn in both mesencephalic neurons and in WT mice striatum. MPTP/MPP ؉ lead to differential alterations in p-Tau and ␣-Syn levels in a cytoskeleton-bound, vs. a soluble, cytoskeleton-free fraction, inducing their coimmunoprecipitation in the cytoskeleton-free fraction and neuronal soma. Subchronic MPTP exposure increased sarkosyl-insoluble p-Tau in striatum of WT but not ␣-Syn؊/؊ mice. These studies describe a novel mechanism for MPTP neurotoxicity, namely a MPTP-inducible, strictly ␣-Syn-dependent, increased formation of PHF-1-reactive Tau, suggesting convergent overlapping pathways in the genesis of clinically divergent diseases such as AD and PD. -Duka, T., Rusnak, M., Drolet, R. E., Duka, V., Wersinger, C., Goudreau, J. L., Sidhu, A. Alphasynuclein induces hyperphosphorylation of Tau in the MPTP model of Parkinsonism. FASEB J. 20, 2302-2312 (2006)
BMC Neuroscience, 2011
Background: α-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. Results: High 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.
Neurodegenerative Diseases, 2008
Background: Mutations in leucine-rich repeat kinase 2 (LRRK2) are thus far the most frequent genetic cause associated with autosomal dominant and idiopathic Parkinson’s disease. Objective:To examine whether LRRK2 is directly associated with the pathological structures of Parkinson’s disease, dementia with Lewy bodies, and other related disorders using highly specific antibodies to LRRK2. Results:LRRK2 antibodies strongly labeled brainstem and cortical Lewy bodies, the pathological hallmarks of Parkinson’s disease and dementia with Lewy bodies, respectively. We found that 20–100% (mean 60%) of α-synuclein-positive Lewy bodies contained LRRK2. While antibodies raised against various regions of LRRK2 were previously shown to label recombinant LRRK2 on Western blots, only antibodies raised against the N- and C-termini, but not the regions containing folded protein domains of LRRK2, immunolabeled Lewy bodies. In Alzheimer’s disease, Hirano bodies were found to contain LRRK2 and the neuro...