Advanced therapeutic for Parkinson's Disease

Parkinson s DiseasePDis a progressive neurodegenerative disorder that affectsmillion patient in the U Sannually andtomillion people worldwidePD is characterized by disorders of movementwhich are caused by the progressive loss of dopamine neurons in the substantia nigra pars compactaSNpcand autonomic dysfunctionanxietydepressionsleep disorders and cognitive impairment that are due to the degeneration and dysfunction of other neuronal populationsTo date there are no pharmaceutical therapies that impede or prevent the neurodegeneration characteristic of the diseaseAlthough dopamine replacement therapy alleviates the symptomatic motor dysfunctionits effectiveness is reduced as the disease progressesleading to unacceptable side effectssuch as severe motor fluctuations and dyskinesiasMoreoverthis palliative therapeutic approach does not address the underlying mechanism sof the diseaseAlthough the etiology of PD is not yet entirely clearthere is an abundance of data indicating that increased oxidative stress in dopaminergic neurons of the SNpc significantly contributes to the pathogenesis of PDc Abl tyrosine kinase has been revealed as a key checkpoint in the brain and c Abl phosphorylationi eactivationis robustly increased in PD brainin animal models ofsynucleinopathies and also in themethylphenyltetrahydropyridineMPTPinduced preclinical animal model of PDActivated c Abl can phosphorylate parkinleading to inhibition of parkin s Eligase function and accumulation of its toxic substratesPARISPARkin Interacting Substrateand aminoacyl tRNA synthetase complex interacting multifunctional proteinAIMPc Ablinhibitors restore parkin s Eligase activityreduce the accumulation of parkin substratesand protects against MPTP induced neurotoxicity in vitro or in vivoActivated c Abl also phosphorylatessynucleindriving bothsynuclein aggregation and production of toxic aggregates that are responsible for neurodegenerationTaken together these results suggest that inhibition of c Abl activation could be an effective disease modifying therapy for PDThe 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