A Novel Genetic Screen Identifies Modifiers of Age-Dependent Amyloid β Toxicity in the Drosophila Brain

MARCORA, MARÍA S.; MORELLI, LAURA; LAUTARO FRANCSICO BELFIORI CARRASCO; CERIANI, M. FERNANDA; BOCAI, NADIA I.; CASTAÑO, EDUARDO M.

Paris

Congreso; ISN-ESN 2017; 2017

ISN

Accumulation ofamyloid β peptide (Aβ) is one of the major hallmarks of Alzheimer´s disease(AD) and its accumulation begins many years before clinical onset. Such processhas been proposed to be pathogenic through the toxicity of Aβ soluble oligomersleading to synaptic dysfunction, phospho-tau aggregation and neuronal loss.Yet, massive accumulation of Aβ can be found in approximately 30% of agedindividuals with preserved cognitive function. Therefore, within the frame ofthe ?amyloid hypothesis?, compensatory mechanisms and additional neurotoxic orprotective factors are the main issues to be elucidated. We carried out amodifier genetic screen in Drosophiladesigned to identify genes that modulate toxicity of Aβ42 in the CNS on agedflies. The expression of Aβ42 led to its accumulation in the brain and amoderate impairment of negative geotaxis at 18 days post-eclosion (d.p.e) ascompared with genetic or parental controls. These flies were mated with acollection of lines carrying chromosomal deletions and negative geotaxis wasassessed at 5 and 18 d.p.e. 199 deficiency lines accounting for ~6300 geneswere analyzed. 6 lines, including the deletion of 52 Drosophila genes with human orthologs, significantly modified Aβ42neurotoxicity at 18 d.p.e. We have validated CG17249 and CG11796 (whose human orthologs are PRCC and HPD,respectively) by using RNAi or mutant hemizygous lines. PRCC encodes proline-rich protein-PRCC of unknown function associated with papillaryrenal cell carcinoma. HPD encodes4-hydroxyphenylpyruvate dioxygenase, a key enzyme in tyrosine degradation whosedeficiency causes autosomal recessive Tyrosinemia type 3, characterized bymental retardation. Our screen is the first to take into account the followingfeatures, relevant to sporadic AD: pan-neuronal expression of wild-type Aβ42; aquantifiable complex behavior; Aβ neurotoxicity associated with progressiveaccumulation of the peptide and improvement or worsening of climbing abilityonly evident in aged animals. These new modifiers of Aβ42 neurotoxicity in Drosophila warrant further study tovalidate their possible role and significance in sporadic AD.