Using Drosophila to identify naturally occurring genetic modifiers of amyloid beta 42- and tau-induced toxicity

Abstract

Alzheimer’s disease (AD) is characterized by two pathological proteins, amyloid beta 42 (Aβ42) and tau. The majority of AD cases in the population are sporadic and late-onset AD (LOAD), which exhibits high levels of heritability. While several genetic risk factors for LOAD have been identified and replicated in independent studies, including the ApoE ε4 allele, the great majority of the heritability of LOAD remains unexplained, likely due to the aggregate effects of a very large number of genes with small effect size, as well as to biases in sample collection and statistical approaches. Here, we present an unbiased forward genetic screen in Drosophila looking for naturally occurring modifiers of Aβ42- and tau-induced ommatidial degeneration. Our results identify 14 significant SNPs, which map to 12 potential genes in 8 unique genomic regions. Our hits that are significant after genome-wide correction identify genes involved in neuronal development, signal transduction and organismal development. Looking more broadly at suggestive hits (P < 10-5), we see significant enrichment in genes associated with neurogenesis, development and growth as well as significant enrichment in genes whose orthologs have been identified as significantly or suggestively associated with AD in human GWAS studies. These latter genes include ones whose orthologs are in close proximity to regions in the human genome that are associated with AD, but where a causal gene has not been identified. Together, our results illustrate the potential for complementary and convergent evidence provided through multi-trait GWAS in Drosophila to supplement and inform human studies, helping to identify the remaining heritability and novel modifiers of complex diseases.

Natural Variation in Age-Related Dopamine Neuron Degeneration is Glutathione-Dependent and Linked to Life Span

“…Multiple studies have demonstrated extensive variation in life span among the DGRP strains (26)(27)(28), consistent with aging heterogeneity in this collection of fly strains that can be leveraged to study age-dependent traits. Indeed, DGRP strains have been shown to vary widely in several parameters associated with aging, including visual senescence (29), decline in fecundity (27,30) and climbing ability (30,31) as well as susceptibility to neurodegeneration triggered by expression of pathogenic proteins such as Ab42 and tau (32) or mutant LRRK2 (33).…”