Neonatal neuronal overexpression of glycogen synthase kinase-3β reduces brain size in transgenic mice

Spittaels, Kurt; Haute, Chris Van den; Dorpe, Jo Van; Terwel, Dick; Vandezande, Kris; Lasrado, Reena; Bruynseels, Koen; Irizarry, Michael C.; Verhoye, Marleen; Lint, Johan Van; Vandenheede, Jackie R.; Ashton, David; Mercken, Marc; Loos, Ruth J.F.; Hyman, Bradley T.; Linden, Annemie Van der; Geerts, Hugo; Leuven, Fred Van

doi:10.1016/s0306-4522(02)00236-1

Cited by 93 publications

(81 citation statements)

References 54 publications

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“…Using a mouse model overexpressing hGSK-3β-S9A under the Thy-1 promoter together with in vitro kinase assays allowed us to discern the role GSK-3β has in the development of PD-like pathology. 43 Analysis of our hGSK-3β-S9A mouse model showed here for the first time that upon aging, these mice develop the cardinal features of parkinsonism, manifested as impaired motor behavior, with associated loss of TH+ neurons, reduced DA production, and shrinkage of SN. Invitro kinase assays confirmed that hGSK-3β was capable of phosphorylating α-Syn on Serine 129 together with the known ability to phosphorylate Tau.…”

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confidence: 77%

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

et al. 2014

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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 studies revealed progressive age-dependent impairment of motor function, accompanied by loss of tyrosine hydroxylase-positive (TH+ DA-neurons) neurons and dopamine production in the oldest age group. Magnetic resonance imaging revealed deterioration of the substantia nigra in aged mice, a characteristic feature of PD patients. At the molecular level, kinase-active p-GSK-3β-Y216 was seen at all ages throughout the brain, yet elevated levels of p-α-Syn-S129 and p-Tau (S396/404) were found to increase with age exclusively in TH+ DA-neurons of the midbrain. p-GSK-3β-Y216 colocalized with p-Tau and p-α-Syn-S129. In vitro kinase assays showed that recombinant human GSK-3β directly phosphorylated α-Syn at a single site, Ser129, in addition to its known ability to phosphorylate Tau. Moreover, α-Syn and Tau together cooperated with one another to increase the magnitude or rate of phosphorylation of the other by GSK-3β. Together, these data establish a novel upstream role for GSK-3β as one of several kinases associated with PTMs of key proteins known to be causal in PD.

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confidence: 77%

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

et al. 2014

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“…For example, overexpression of GSK-3␤ in the central nervous system of developing mice results in a reduction in the size of the brain and spinal cord (46), and GSK-3␤ gene disruption causes embryonic lethality (33). During the aging of human fibroblasts, the active form of GSK-3␤ accumulates in the nucleus in association with p53, causing replicative senescence (51).…”

Section: Discussionmentioning

confidence: 99%

Regulation and Function of Glycogen Synthase Kinase-3 Isoforms in Neuronal Survival

Liang

Chuang

2007

Journal of Biological Chemistry

126

102

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Glycogen synthase kinase-3 (GSK-3) is a serine/threonine kinase consisting of two isoforms, ␣ and ␤. ⌻he activities of GSK-3 are regulated negatively by serine phosphorylation but positively by tyrosine phosphorylation. GSK-3 inactivation has been proposed as a mechanism to promote neuronal survival. We used GSK-3 isoform-specific small interfering RNAs, dominant-negative mutants, or pharmacological inhibitors to search for functions of the two GSK-3 isoforms in regulating neuronal survival in cultured cortical neurons in response to glutamate insult or during neuronal maturation/aging. Surprisingly, RNA interference-induced depletion of either isoform was sufficient to block glutamate-induced excitotoxicity, and the resulting neuroprotection was associated with enhanced N-terminal serine phosphorylation in both GSK-3 isoforms. However, GSK-3␤ depletion was more effective than GSK-3␣ depletion in suppressing spontaneous neuronal death in extended culture. This phenomenon is likely due to selective and robust inhibition of GSK-3␤ activation resulting from GSK-3␤ Ser 9 dephosphorylation during the course of spontaneous neuronal death. GSK-3␣ silencing resulted in reduced tyrosine phosphorylation of GSK-3␤, suggesting that tyrosine phosphorylation is also a critical autoregulatory event. Interestingly, GSK-3 inhibitors caused a rapid and long-lasting increase in GSK-3␣ Ser 21 phosphorylation levels, followed by a delayed increase in GSK-3␤ Ser 9 phosphorylation and a decrease in GSK-3␣ Tyr 279 and GSK-3␤ Tyr 216 phosphorylation, thus implying additional levels of GSK-3 autoregulation. Taken together, our results underscore important similarities and dissimilarities of GSK-3␣ and GSK-3␤ in the roles of cell survival as well as their distinct modes of regulation. The development of GSK-3 isoform-specific inhibitors seems to be warranted for treating GSK-3-mediated pathology.

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“…Besides its role in circadian rhythms, GSK3β is a widely expressed kinase that has many functions in the brain (Jope and Roh, 2006). Furthermore, it is unclear as to what brain region is involved in the manic-like behaviors since the transgene is expressed in several regions, or if this overexpression affects circadian rhythms or the regulation of circadian genes (Spittaels et al, 2002). One reason to suspect that the manic-like phenotype seen in these mice may involve the circadian clock is that our laboratory has found that mice harboring a mutation in the CLOCK gene also display a behavioral profile that is strikingly similar to human mania (Roybal et al, in press).…”

Section: Behavioral Studiesmentioning

confidence: 99%

Circadian genes, rhythms and the biology of mood disorders

McClung

2007

Pharmacology & Therapeutics

576

386

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For many years, researchers have suggested that abnormalities in circadian rhythms may underlie the development of mood disorders such as bipolar disorder, major depression and seasonal affective disorder. Furthermore, some of the treatments that are currently employed to treat mood disorders are thought to act by shifting or "resetting" the circadian clock, including total sleep deprivation and bright light therapy. There is also reason to suspect that many of the mood stabilizers and antidepressants used to treat these disorders may derive at least some of their therapeutic efficacy by affecting the circadian clock. Recent genetic, molecular and behavioral studies implicate individual genes that make up the clock in mood regulation. As well, important functions of these genes in brain regions and neurotransmitter systems associated with mood regulation is becoming apparent. In this review, the evidence linking circadian rhythms and mood disorders, and what is known about the underlying biology of this association, is presented.

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Neonatal neuronal overexpression of glycogen synthase kinase-3β reduces brain size in transgenic mice

Cited by 93 publications

References 54 publications

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

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

Regulation and Function of Glycogen Synthase Kinase-3 Isoforms in Neuronal Survival

Circadian genes, rhythms and the biology of mood disorders

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