Deciphering Genetics of PLCG2 Alternative Splicing to Understand AD Risk

Grants and Contracts Details


A critical barrier in translating Alzheimer’s disease (AD) genetic progress to pharmacologic strategy is elucidating the molecular mechanisms whereby genetic variants impact gene expression and function to impact AD risk. This proposal focuses on PLCG2, a gene strongly associated with AD thru a PLCG2 missense single nucleotide polymorphism (SNP), rs72824905, (P522R), that acts to reduce AD risk. The SNP was subsequently identified as also being protective for Lewy Body dementia and frontotemporal dementia. PLCG2 is one of the genes that mediates the downstream signaling from TREM2, a primary AD risk gene. Although P522R appears to increase PLCG2 function, homozygosity for P522R appears deleterious to humans, suggesting that optimal PLCG2 activity must be tightly controlled. In considering the role of PLCG2 in AD, we realized that a careful scrutiny of PLCG2 splicing and expression relative to genetics has not been described. Indeed, a recent genome wide association study identified a SNP near PLCG2 as AD-associated but the actions of SNP relative to PLCG2 are unclear. Here, we propose to delve into PLCG2 molecular genetics to elucidate the mechanisms whereby genetics modulate PLCG2 expression and splicing to impact AD risk. In preliminary work, we identified a PLCG2 splice variant in human brain that lacks 65bp within exon 28. We quantified this isoform in a series of AD and non-AD brain samples and identified a SNP within exon 28 that is associated with the proportion of PLCG2 expressed as this novel isoform. Remarkably, this SNP appears associated with AD risk (p=10-8). Testing this SNP in a minigene format supports the hypothesis that this SNP is functional. Lastly, we have identified splicing factors that improve PLCG2 exon 28 splicing in a fashion that would be predicted to reduce AD risk, suggesting that these findings have translational potential. Hence, our global hypothesis is that genetic regulators of PLCG2 splicing and/or expression modulate AD risk. To explore this hypothesis, we propose the following Specific Aims: Identify PLCG2 isoforms expressed in human brain and quantify these isoforms as a function of AD neuropathology and genetics. Specific Aim 2: Compare PLCG2 and D65-PLCG2 protein expression and function. Specific Aim 3: Translate PLCG2 splicing genetics to identify modulators that would reduce AD risk. Successful completion of these studies will identify rs1071644 as novel SNP for AD risk, demonstrate functionality of this SNP, and provide novel insights into the impact quantified differences in PLCG2 splicing on AD risk.
Effective start/end date4/15/243/31/26


  • National Institute on Aging: $415,626.00


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