Project Grant R21AG085108

MECHANISTIC INVESTIGATION OF INNATE IMMUNITY IN A DROSOPHILA MODEL OF FRONTOTEMPORAL DEMENTIA - FRONTOTEMPORAL DEMENTIA (FTD) IS THE SECOND MOST COMMON PRESENILE DEMENTIA AFTER ALZHEIMER'S DISEASE AND SHARES MANY PATHOLOGICAL AND GENETIC OVERLAPS WITH ALS. THE MOST COMMON GENETIC CAUSE OF FTD AND ALS IS A GGGGCC HEXANUCLEOTIDE REPEAT EXPANSION IN THE FIRST INTRON OF THE C9ORF72 GENE. ALTHOUGH RNA TOXICITY AND C9ORF72 HAPLOINSUFFICIENCY MAY ALSO CONTRIBUTE TO DISEASE PATHOGENESIS IN C9ORF72-RELATED FTD/ALS, MUCH EFFORTS HAS FOCUSED ON INVESTIGATING THE TOXICITY OF DIPEPTIDE REPEAT (DPR) PROTEINS THAT CAN BE TRANSLATED FROM BOTH SENSE AND ANTISENSE REPEAT RNAS. HOW THESE DPR PROTEINS, ESPECIALLY POLY(GR), CAUSE NEURODEGENERATION AT THE MOLECULAR MECHANISTIC LEVEL REMAINS LARGELY UNKNOWN. IN THIS EXPLORATORY R21 GRANT APPLICATION, BASED ON OUR RECENT FINDINGS THAT SEVERAL ANTIMICROBIAL PEPTIDE GENES, SUCH AS METCHNIKOWIN (MTK), ARE UPREGULATED WITH POLY(GR) TOXICITY IN DROSOPHILA AND THAT MTK KNOCKDOWN IN THE EYE OR IN ALL NEURONS SUPPRESSES POLY(GR) NEUROTOXICITY, WE PROPOSE TO FURTHER INVESTIGATE THIS UNDERSTUDIED PATHWAY IN NEURODEGENERATION. IN PARTICULAR, WE WILL INVESTIGATE THE MOLECULAR MECHANISMS UNDERLYING THE EFFECTS OF MTK ON POLY(GR) TOXICITY, EXPLORE THE NON-CELL AUTONOMOUS NEURODEGENERATIVE ACTIVITY OF MTK, AND FINALLY ATTEMPT TO IDENTIFY MAMMALIAN AMP(S) THAT MAY FUNCTION IN A SIMILAR FASHION AS DROSOPHILA MTK IN THE MOLECULAR PATHOGENESIS OF FTD/ALS. THESE STUDIERS WILL SHED NEW LIGHT ON PATHOGENIC MECHANISMS OF FTD/ALS AND MAY HELP IDENTIFY NOVEL THERAPEUTIC TARGETS FOR THESE DISORDERS.