3-nitropropionic acid (3-NP) is a well-documented naturally occurring potent neurotoxin produced by certain plants and fungi causing livestock as well as human poisonings. 3-NP irreversibly inhibits succinate dehydrogenase (SDH), the main constituent of the mitochondrial respiratory chain complex II, leading to impairedmitochondrialbioenergeticsandneuronalcelldeath,predominantlyinthestriatum.Inrecentyears,a new generation of fungicides that act via inhibition of mitochondria complex II succinate dehydrogenase has beenintroducedintothemarkets.Althoughoccupationalexposureorgeneralconsumptionofeitherlivestock, raw produce, or processed food contaminated with inhibitors of SDH may not pose a serious health risk to healthyindividuals,evenlowamountsmightinfluencetheclinicalandpathologicalmanifestationinindividuals already predisposed to neurodegenerative diseases where mitochondrial function is compromised. Mitochondrial dysfunction occurs in the aging brain as well as in a number of neurodegenerative disorders, including the alpha-synucleopathies Multiple System Atrophy and Parkinson?s Disease, the polyglutamine disordersHuntington?sDiseaseandMachado-JosephDisease,AmyotrophicLateralSclerosis,andAlzheimer?s Disease. Both environmental factors and genetic modifiers are thought to play essential roles in these and otherneurodegenerativedisorders.Thelong-termobjectiveofthisworkistoidentifygeneticmodifiersof3-NP neurotoxicityusinginbredBXDmiceforthemappingoflocithatcontributetosusceptibilityorresistanceto3- NP-inducedneuronalcelldeath.OurpreliminarydataindicatethattheparentalstrainC57BL/6Jissusceptible whereas DBA/2J is resistant to 3-NP-induced neuronal injury, justifying the use of BXDs for our purposes. Identifying genetic pathways that provide neuroprotection to 3-NP will be invaluable for uncovering potential genetic modulators of 3-NP neurotoxicity, shedding light on mechanisms of susceptibility associated with exposure to this neurotoxin. In addition, our findings will provide further understanding of the disease processesinneurodegenerativedisordersassociatedwithmitochondriadysfunction,andleadtonewlinesof researchonpreventionandtherapeutics.
3-nitropropionicacid(3-),apotentinhibitorofsuccinatedehydrogenase,isanaturallyoccurringneurotoxin producedbyplantsandfungicausinglivestockandhumanpoisonings.Inthisapplicationweproposeto identifygeneticfactorsthatconferresistancetoneuronalcelldeathupon3-NPadministration.Ourfindingswill leadtotheidentificationofgeneticmodifiersofneurodegenerativedisordersassociatedwithmitochondria dysfunctionandthedevelopmentofnewandmoreeffectivetherapeutictreatmentsforthese neurodegenerativedisorders.
