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

Abstract

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.

Differential degradation of motor deficits during gradual dopamine depletion with 6-hydroxydopamine in mice

“…To assess fine motor coordination in gradually depleted mice, animals were subjected to a pole task. While less commonly utilized than open field and rearing, the pole task is a well-established technique used to assess motor skills in many animal models of diseases that result in motor dysfunction (Matsuura, Kabuto et al 1997, Hickey, Kosmalska et al 2008, Credle, George et al 2014). The task involves placing an animal face upward on a tall vertical pole with small diameter (1 cm) and measuring the time it takes for the animal to turn facing downward (Turn down latency = TDL), the time from turning downward to finish traversing the pole (Traverse), and the total time spent on the pole (Total) (Fig.…”

Tau Positron Emission Tomographic Imaging in the Lewy Body Diseases

“…Whether Aβ is necessary for tau accumulation in LBD remains to be determined, however, as small foci of cortical amyloid were present in some cases, as previously demonstrated in LBD (9), and soluble Aβ oligomers and non-fibrillar amyloid in diffuse plaques could also contribute (7). This distinction between AD and the LBD may reflect the synergistic relationship between α-synuclein aggregation and tau pathology (49,50). …”

Aberrant regulation of the GSK ‐3β/ NRF 2 axis unveils a novel therapy for adrenoleukodystrophy

“…Future work should address and quantify both the functionality of the NRF2 pathway in rhizomelic chondrodysplasia punctata and the AKT/GSK‐3β/NRF2 axis in other peroxisomal disorders, given the possibility of targeted treatments like DMF, for these metabolic diseases. Increased GSK‐3β also occurs in other neurodegenerative conditions, like tauopathies, in which GSK‐3β is one of the kinases responsible for pathological phosphorylation of Tau (Llorens‐Martin et al , ); Parkinson's disease (Duka et al , ; Credle et al , ) or multiple sclerosis (Beurel et al , ).…”