Identification of Novel Genes That Modify Phenotypes Induced by Alzheimer's β-Amyloid Overexpression in Drosophila

Abstract

Sustained increases in life expectancy have underscored the importance of managing diseases with a high incidence in late life, such as various neurodegenerative conditions. Alzheimer's disease (AD) is the most common among these, and consequently significant research effort is spent on studying it. Although a lot is known about the pathology of AD and the role of b-amyloid (Ab) peptides, the complete network of interactions regulating Ab metabolism and toxicity still eludes us. To address this, we have conducted genetic interaction screens using transgenic Drosophila expressing Ab and we have identified mutations that affect Ab metabolism and toxicity. These analyses highlight the involvement of various biochemical processes such as secretion, cholesterol homeostasis, and regulation of chromatin structure and function, among others, in mediating toxic Ab effects. Several of the mutations that we identified have not been linked to Ab toxicity before and thus constitute novel potential targets for AD intervention. We additionally tested these mutations for interactions with tau and expanded-polyglutamine overexpression and found a few candidate mutations that may mediate common mechanisms of neurodegeneration. Our data offer insight into the toxicity of Ab and open new areas for further study into AD pathogenesis

<i>In Vivo</i> Screening of Traditional Medicinal Plants for Neuroprotective Activity against Aβ42 Cytotoxicity by Using <i>Drosophila</i> Models of Alzheimer’s Disease

“…8,15,16) Moreover, as Drosophila AD models show various and easily-quantifiable phenotypes, such as eye degeneration, developmental defects, shortened lifespan, locomotor defects, increased oxidative stress sensitivity, and learning and memory defects, they have been employed for finding genetic modifiers of AD-associated genes. [17][18][19][20][21][22][23] In addition, Drosophila AD models have been used to search and evaluate possible candidate drugs for AD. 8) Recently, usage of Drosophila models has been extended to test the efficacy of traditional medicines, and successfully played a role in the analysis of their action mechanism at the molecular level.…”

Viability, Longevity, and Egg Production of Drosophila melanogaster Are Regulated by the miR-282 microRNA

“…The latter notion is further supported by our findings that the mir-282 gene is active at the pupal stage and it is conserved in holometabolic insects, which undergo complete metamorphosis. Moreover, in genetic interaction screens, mir-282 overexpression was found to have effect on pupal wing development and nervous system function (Bejarano et al 2008;Cao et al 2008).…”

Steroid metabolism in cnidarians: Insights from Nematostella vectensis

“…In mammals, 17β-HSD 10 also binds β-amyloid proteins and may play a role in neurodegenerative diseases, such as Alzheimer's disease. The neural role of β-amyloid proteins is phylogenetically conserved (Cao et al, 2008;Niwa et al, 2008), although it is not known whether the interactions between 17β-HSD 10 and β-amyloid proteins are similarly conserved. Lethal phenotypes associated with scully (D. melanogaster gene homologous to HSD17B10) mutants indicate an essential role of 17β-HSD 10 in β-oxidation of lipids in gonadal and neural tissues (Torroja et al, 1998).…”