The protein GSK-3beta has not previously been linked to Parkinson’s disease (PD). Recently, we have studied pre-clinical models with high levels of GSK-3beta throughout the brain. At a younger age [up to 9 months], these models do not show any PD-like symptoms, such as abnormal motor movements. Upon aging, however, similar to humans, these GSK-3beta models gradually develop difficulties in movement (at 12-15 months of age). Moreover, pathological changes occur in the brain of 15-month-old models that mirror changes seen in PD in humans, and such changes are only seen in those brain regions that are affected in PD. The changes include increased levels of toxic proteins (alpha-synuclein and phosphorylated tau) associated with PD. We have also observed considerable loss in dopamine-producing cells in the 15-month-old model. Interestingly, there is no loss in cells that do not produce dopamine.
Project Description:
In this project we will analyze models at 12, 15 and 18 months of age. At each stage we will conduct a battery of behavior tests to assess the development of abnormal motor function, including walking and coordination skills. We will then examine the brains of the models to assess if there is loss in dopamine-producing neurons and diminished levels of dopamine. We will next examine toxic proteins linked to GSK-3beta, including alpha-synuclein and phosphorylated tau. From these studies, we will gain valuable and detailed information of the precise changes that occur in brains of these models, and will be able to assess any worsening of behavior and brain pathology as they age.
Relevance to Diagnosis/Treatment of Parkinson’s Disease:
GSK-3beta may prove to be useful in the development of biomarkers for PD, either through a simple blood test or by examining spinal fluids. This will inform us of populations that may be at risk for PD. Additionally, novel drugs could be developed that target GSK-3beta and lower its levels in the brain, thereby modifying disease progression.
Anticipated Outcome:
We expect that at 12 months of age, only minor pathological changes in the brain and in behavior will occur, and that such changes will worsen as the pre-clinical model ages to 15 months. At 18 months of age, there will be an even greater loss of motor behavior, considerable loss of dopamine producing neurons and elevated levels of alpha-synuclein and phosphorylated tau in the brain, which will hamper normal brain function.
Final Outcome
In order to examine the role of GSK-3beta in Parkinson’s disease [PD], we studied pre-clinical models overexpressing a kinase-active form of this protein, GSK-3beta-S9A, in the brain. Our results showed that the age of onset, severity and progression of Parkinson’s disease in these models closely mirrored that seen in humans. While young pre-clinical models did not have any deficits, pre-clinical models that were 12 months or older started showing symptoms of the disease, which worsened with age (up to 18 months). Similar to humans, these pre-clinical models showed shrunken Substantia nigra, loss of TH+ neurons and loss of dopamine production. Moreover, we found that GSK-3beta was able to directly phosphorylate alpha-synuclein, generating a highly toxic form of this protein, p-alpha-synuclein-S129. Furthermore, we found that another protein phosphorylated by GSK-3beta, Tau, was phosphorylated at sites that were virtually identical to sites seen in postmortem PD brains. As in humans, the motor deficits seen in 18-month old pre-clinical models could be reversed by treatment with levodopa. These combined data show that GSK-3beta participates in the genesis of PD and may provide a new target for the treatment of this disease, via inhibition of this protein.
Posters and Presentations
Credle JJ, George JL, Wills J, Duka V, Shah K, Lee YC, Rodriguez O, Simkins T, Winter M, Moechars D, Steckler T, Goudreau J, Finkelstein DI, Sidhu A. GSK-3β dysregulation contributes to parkinson's-like pathophysiology with associated region-specific phosphorylation and accumulation of tau and α-synuclein. Cell Death Differ. 2014 Nov 14. doi: 10.1038/cdd.2014.179.