A novel genetic screen identifies modifiers of agedependent amyloid b toxicity in the drosophila brain

BELFIORI-CARRASCO, LAUTARO F.; MARCORA, MARÍA S.; BOCAI, NADIA I.; CERINAI, MF; MORELLI L; CASTAÑO E.M

Paris

Congreso; 26th Biennial Meeting of the International Society for Neurochemistry (ISN).; 2017

ISN

Accumulation of amyloid b peptide (Ab) is one of the majorhallmarks of Alzheimer0s disease (AD) and its accumulation beginsmany years before clinical onset. Such process has been proposed tobe pathogenic through the toxicity of Ab soluble oligomers leadingto synaptic dysfunction, phospho-tau aggregation and neuronal loss.Yet, massive accumulation of Ab can be found in approximately30% of aged individuals with preserved cognitive function.Therefore, compensatory mechanisms and additional neurotoxic orprotective factors are the main issues to be elucidated. We carriedout a modifier genetic screen in Drosophila designed to identifygenes that modulate toxicity of Ab42 in the CNS on aged flies.Expression of Ab42 led to its accumulation in the brain and amoderate impairment of negative geotaxis at 18 days post-eclosion(d.p.e) as compared with genetic or parental controls. These flieswere mated with a collection of lines carrying chromosomaldeletions and negative geotaxis was assessed at 5 and 18 d.p.e.199 deficiency lines accounting for ~6300 genes were analyzed. 6lines, including the deletion of 52 Drosophila genes with humanorthologs, significantly modified Ab42 neurotoxicity at 18 d.p.e. Wehave validated CG17249 and CG11796 (whose human orthologs arePRCC and HPD, respectively) by using RNAi or mutant hemizygous lines. PRCC encodes proline-rich protein-PRCC of unknown function associated with papillary renal cell carcinoma. HPD encodes 4-hydroxyphenylpyruvate dioxygenase, a key enzyme in tyrosine degradation whose deficiency causes autosomal recessive Tyrosinemia type 3, characterized by mental retardation. Our screen is the first to take into account features relevant to sporadic AD: panneuronal expression of wild-type Ab42; a quantifiable complex behavior; Ab neurotoxicity associated with progressive accumulation of the peptide and improvement or worsening of climbing ability only evident in aged animals. These new modifiers of Ab42 neurotoxicity in Drosophila warrant further study to validate their possible role and significance in sporadic AD