Research Project
9549150
Parkinson's Disease (PD) is a progressive neurodegenerative disorder that affects ?1 million patient in the U.S. annually and 7 to 10 million people worldwide. PD is characterized by disorders of movement, which are caused by the progressive loss of dopamine neurons in the substantia nigra pars compacta (SNpc), and autonomic dysfunction, anxiety, depression, sleep disorders and cognitive impairment that are due to the degeneration and dysfunction of other neuronal populations. To date there are no pharmaceutical therapies that impede or prevent the neurodegeneration characteristic of the disease. Although dopamine replacement therapy alleviates the symptomatic motor dysfunction, its effectiveness is reduced as the disease progresses, leading to unacceptable side effects, such as severe motor fluctuations and dyskinesias. Moreover, this palliative therapeutic approach does not address the underlying mechanism(s) of the disease. Although the etiology of PD is not yet entirely clear, there is an abundance of data indicating that increased oxidative stress in dopaminergic neurons of the SNpc significantly contributes to the pathogenesis of PD. c-Abl tyrosine kinase has been revealed as a key checkpoint in the brain and c-Abl phosphorylation (i.e. activation) is robustly increased in PD brain, in animal models of ?-synucleinopathies and also in the 1-methyl-4-phenyl-1,2,3,6- tetrahydropyridine (MPTP)-induced preclinical animal model of PD. Activated c-Abl can phosphorylate parkin, leading to inhibition of parkin's E3 ligase function and accumulation of its toxic substrates, PARIS (PARkin Interacting Substrate) and aminoacyl tRNA synthetase complex-interacting multifunctional protein 2 (AIMP2). c-Abl1/2 inhibitors restore parkin's E3 ligase activity, reduce the accumulation of parkin substrates, and protects against MPTP-induced neurotoxicity in vitro or in vivo. Activated c-Abl also phosphorylates ?- synuclein, driving both ?-synuclein aggregation and production of toxic aggregates that are responsible for neurodegeneration. Taken together these results suggest that inhibition of c-Abl activation could be an effective disease modifying therapy for PD. The present proposal will analyze the pharmacological properties of a series of novel c-Abl inhibitors and demonstrate their efficacy in a mouse model of progressive neurodegeneration.
