Early onset intellectual disabilities (ID) affect 1-3% of the population and results in a major burden to familiesandsociety,withlifetimecostsestimatedtobe$1-2million.Therearemanycauses,someof which are preventable such as malnutrition and fetal alcohol syndrome. However, the most severe formsofIDhavegeneticcauses,andapproximately25%ofallcaseshavebeenmappedtochromo- somal deletions, rearrangements, and mutations. X-linked intellectual disabilities (XLIDs) account for approximately10-12%ofmaleIDcases.Identificationoftheresponsiblegenesholdsoutthepromise that having an inventory of potentially defective genes, and understanding the molecular defects will lead to better tests and treatments to help patients and their families. Several ID mutations (X-linked andautosomal)havebeenmappedtomembersofafamilyofproteinacyltransferase(PAT)enzymes that our group discovered and is characterizing. They are referred to as zDHHC PATs, named for a conserved sequence motif in the active site of the enzyme (Asp-His-His-Cys). Mutations in zDHHC geneshavebeenlinkedtocolorectalandleukomyloidcancers,cardiovasculardisease,infectiousdis- eases,andneurologicaldisorders.Despitethegrowingappreciationoftheroleofpalmitoylationincell physiology, the molecular mechanism of palmitoylation and depalmitoylation, substrate selection, and regulationofpalmitoyltransferactivityrequiresfurtherstudy.Theproposedstudieswilllaytheground- workforfuturestudiesaimedatclarifyingthelinkbetweenzDHHC9mutationsandXLIDandforunder- standingthemolecularmechanismsthatlinkpalmitoylationtodiseaseingeneral.Wewillaccomplish thesegoalsbypursuingtwospecificaims:(1)IdentificationofzDHHC9palmitoylatedsubstratesinneu- rons;?and(2)DeterminehowalteredpalmitoylationcausesneuronaldefectsthatcanleadtoX-Linked IntellectualDisability(XLID).Successfulcompletionofthesestudieswillincreaseourunderstandingof theroleofproteinlipidationincellularregulationduringhealthanddisease.Theproposedresearchis innovativebecauseofthenewtechniqueswewillusetoprobethemechanismofactionofanewfamily ofenzymescentraltotheestablishmentofspatialregulationofsignalingnetworks.
Protein palmitoylation is a posttranslational modification that is involved in a diverse array of cellular processesincluding,butnotlimitedto,signaltransduction,proteintrafficking,proteinturnover,andves- icle fusion. Dysregulation of protein palmitoylation plays an important role in the etiology of many dis- eases,includingX-LinkedIntellectualDisabilities(XLID).However,thereiscurrentlyinsufficientinfor- mationabouthowpalmitoylationregulatesneuronaltodeveloptherapeuticstrategies,andthisproposal willfillthatgapinknowledge.
| Hamel, Laura D; Lenhart, Brian J; Mitchell, David A et al. (2016) Identification of Protein Palmitoylation Inhibitors from a Scaffold Ranking Library. Comb Chem High Throughput Screen 19:262-74 |
| Reddy, Krishna D; Malipeddi, Jashwanth; DeForte, Shelly et al. (2016) Physicochemical sequence characteristics that influence S-palmitoylation propensity. J Biomol Struct Dyn :1-14 |
