There is increasing evidence that Parkinsons disease (PD) is intricately linked to mitochondrial abnormalities: familial forms of the disease are linked to mitochondrial quality control proteins PINK1, Parkin, and Fbxo7; mitochondria of DA neurons have the highest rates of mtDNA mutations; and small molecule mitochondrial toxins produce preferential degeneration of dopaminergic neurons in mice. PTEN Induced Kinase 1 (PINK1) is a master regulator of mitochondrial quality control. In the presence of a depolarized mitochondrion, PINK1 is stabilized on the outer mitochondrial membrane, where it recruits and phosphorylates ubiquitin and Parkin, blocks mitochondrial fusion and trafficking and ultimately triggers mitochondrial autophagy. Further, PINK1 can drive mitochondrial biogenesis by directly phosphorylating PARIS, and can oppose alpha-?synuclein and amyloid toxicity and proteotoxic stress more generally. Genetic manipulations that drive accumulation of damaged mitochondria have a significant effect on cell health, leading us to believe that mitochondrial problems in the dopaminergic neurons of the substantia nigra may be causing energy failure and/or an increased generation of reactive oxygen species, and ultimately neuronal death. This hypothesis appears to be further supported by the fact that more than 50 mutations in the kinase PINK1 have been associated with the development of autosomal recessive PD. In addition, overexpression of wild-?type PINK1, but not the catalytically compromised PD-?associated PINK1G309D mutant can rescue this defect in mitophagy and protect cells from oxidative stress. Our founding team discovered that it is possible to selectively amplify PINK1 activity through a novel neo-? substrate mechanism. The downstream consequences of amplified PINK1 activity can be seen in higher rates of Parkin recruitment to stressed mitochondria, reduced mitochondrial motility, and, ultimately, lower levels of apoptosis vs. healthy controls. This therapeutic strategy is that it doesnt interfere with PINK1s endogenous regulation; rather, it only amplifies PINK1 activity when PINK1 is stabilized on a depolarized mitochondrion. We believe that the pharmacological amplification of PINK1 kinase activity, acting through the clearance of defective mitochondria and PINK1-?related suppression of apoptosis, could prove a powerful mechanism through which to treat PD. In this SBIR project we will conduct lead optimization. We have already made great strides in our chemistry program, significantly boosting the oral PK properties and potency of our PINK1 neo-?substrates. We believe that by the end of this grant we will have identified a molecule suitable for final proof of concept in vivo studies, with IND enabling studies to follow.
Public Health Relevance Statement: Public Health Relevance Parkinsons disease affects over 1,000,000 Americans, a number thats expected to grow significantly by 2040. According to a study published in Movement Disorders (2013), the United States already suffers more than $14.4 billion in annual economic losses owing to the disease, and that analysis excludes the impact on caregivers and families. We aim to develop the first disease-?modifying therapy for Parkinsons disease, reducing the strain of PD on Americas healthcare system and ensuring a higher quality of life of patients and their families.
Project Terms: Affect; Age; alpha synuclein; American; Americas; Amplifiers; Amyloid; Apoptosis; Biogenesis; Biological Assay; Biology; Blood; Blood - brain barrier anatomy; Brain; candidate selection; Caregivers; cell motility; Cells; Cellular Stress; Chemistry; Clinical Research; Defect; Development; Disease; Disease model; Disease Progression; dopaminergic neuron; Dose; Drug Kinetics; early onset; Economics; end stage disease; Ensure; Failure; Family; FBXO7 gene; Generations; genetic manipulation; Goals; Grant; Health; Healthcare Systems; improved; In Vitro; in vivo; in vivo Model; Individual; innovation; Kinetins; Lead; lead optimization; Levodopa; Link; member; Mitochondria; mitochondrial autophagy; mitochondrial DNA mutation; Movement Disorders; Mus; mutant; Mutation; N6-furfuryladenine; Neurodegenerative Disorders; neuron loss; next generation; novel; nucleobase analog; Oral; Outer Mitochondrial Membrane; overexpression; Oxidative Stress; parkin gene/protein; Parkinson Disease; Pathology; Pathway interactions; Patients; Penetrance; Pharmacology; Phase; Phosphotransferases; Plasma; Population; programs; Property; proteotoxicity; PTEN gene; PTEN protein; public health relevance; Publishing; Quality Control; Quality of life; Reactive Oxygen Species; recruit; Regulation; response; Risk; Series; Small Business Innovation Research Grant; small molecule; Stress; Structure-Activity Relationship; Substantia nigra structure; symptom management; Therapeutic; therapeutic target; Toxic effect; Toxin; trafficking; Ubiquitin; United States; United States National Institutes of Health; Vendor
