Neo-Substrate Amplifiers of PINK1 for the Treatment of Parkinsons Disease

ABSTRACTThereisincreasingevidencethatParkinson sdiseasePDisintricatelylinkedtomitochondrialabnormalitiesfamilialformsofthediseasearelinkedtomitochondrialqualitycontrolproteinsPINKParkinandFbxomitochondriaofDAneuronshavethehighestratesofmtDNAmutationsandsmallmoleculemitochondrialtoxins produce preferential degeneration of dopaminergic neurons in micePTEN Induced KinasePINKis amasterregulatorofmitochondrialqualitycontrolInthepresenceofadepolarizedmitochondrionPINKisstabilizedontheoutermitochondrialmembranewhereitrecruitsandphosphorylatesubiquitinandParkinblocks mitochondrial fusion and trafficking and ultimately triggers mitochondrial autophagyFurtherPINKcandrive mitochondrial biogenesis by directly phosphorylating PARISand can oppose alphasynuclein and amyloidtoxicity and proteotoxic stress more generallyGenetic manipulations that drive accumulation of damaged mitochondria have a significant effect on cell healthleading us to believe that mitochondrial problems in the dopaminergic neurons of the substantia nigra may becausingenergyfailureand oranincreasedgenerationofreactiveoxygenspeciesandultimatelyneuronaldeathThis hypothesis appears to be further supported by the fact that more thanmutations in the kinasePINKhavebeenassociatedwiththedevelopmentofautosomalrecessivePDInadditionoverexpressionofwildtypePINKbutnotthecatalyticallycompromisedPDassociatedPINK GDmutantcanrescuethisdefect in mitophagy and protect cells from oxidative stressOurfoundingteamdiscoveredthatitispossibletoselectivelyamplifyPINKactivitythroughanovelneosubstratemechanismThe downstream consequences of amplified PINKactivity can be seen in higher ratesof Parkin recruitment to stressed mitochondriareduced mitochondrial motilityandultimatelylower levels ofapoptosisvshealthycontrolsThistherapeuticstrategyisthatitdoesn tinterferewithPINKsendogenousregulationratherit only amplifies PINKactivity when PINKis stabilized on a depolarized mitochondrionWebelieve that the pharmacological amplification of PINKkinase activityacting through the clearance of defectivemitochondriaandPINKrelatedsuppressionofapoptosiscouldproveapowerfulmechanismthroughwhichto treat PDInthisSBIRprojectwewillconductleadoptimizationWehavealreadymadegreatstridesinourchemistryprogramsignificantly boosting the oral PK properties and potency of our PINKneosubstratesWe believe thatby the end of this grant we will have identified a molecule suitable for final proof of concept in vivo studieswithIND enabling studies to followPublic Health RelevanceParkinson s disease affects overAmericansa number that s expected to growsignificantly byAccording to a study published in Movement Disordersthe UnitedStates already suffers more than $billion in annual economic losses owing to the diseaseand that analysis excludes the impact on caregivers and familiesWe aim to develop the firstdiseasemodifying therapy for Parkinson s diseasereducing the strain of PD on America shealthcare system and ensuring a higher quality of life of patients and their families