Therapeutic effects of brain-penetrable kinase inhibitors to prevent accumulation of pathogenic alpha-synuclein oligomers in Parkinson’s disease
Description: Background: Parkinson’s disease (PD) is a neurodegenerative disorder in the elderly characterized by aggregates of misfolded alpha-synuclein in Lewy bodies and loss of dopaminergic neurons in the brain. Over half of the total dopaminergic neurons are loss when symptoms first occur with no cure. Developing early preventive therapy is crucial to slow disease progression. The soluble alpha-synuclein oligomers (or protofibrils) are toxic to mediate the pathogenesis of PD. Phosphorylated alpha-synuclein can affect the propensity of its own aggregation.
Objectives: To determine the correlation between alpha-synuclein phosphorylation and the propensity to form toxic oligomers in neurons, and to determine the therapeutic effects of three brain-penetrable kinase inhibitors - Nilotinib, Saracatinib, and GNE-7915, on alpha-synuclein phosphorylation in mouse brains.
Hypothesis: Pharmacological inhibition of kinases to suppress alpha-synuclein phosphorylation may attenuate buildup of toxic oligomers in the brain as a viable preventive therapy to slow PD progression.
Subjects: Wildtype & LRRK2(R1441G) mutant knockin mice and their primary cortical neurons
Methods: Levels of phosphorylated alpha-synuclein and its oligomer in neuronal cell lysates will be quantified by Western blotting and ELISA. Young mice will be injected with three kinase inhibitors for 26 weeks to reduce buildup of toxic alpha-synuclein oligomer in the aging brains.
Expected outcome: We expect to determine the drug efficacy (EC50) of three brain-penetrable kinase inhibitors for early preventive therapeutic intervention to attenuate brain accumulation of alpha-synuclein oligomer at initial stages of PD, and to develop an in-vivo screening platform to repurpose existing drugs for anti-Parkinsonian drug discovery.
Funder: Health and Medical Research Fund
Amount: HKD 1,176,000
Funding type: grant
Funder scheme: HMRF - Advanced Medical Research
Start date: 2016-01-01
Investigator: Wing Lok Philip HO
Institution: Department of Medicine, The University of Hong Kong
Funded outputs count: 2
Funder award ID: 05161856
OpenAlex ID: G5986332435