enabled downregulation impairs axonal transport leading to neurodegeneration

C REZÁVAL AND MF CERIANI

Los Cocos, Córdoba

Congreso; XXII Congreso de la Sociedad Argentina de Investigación en Neurociencias (SAN); 2007

Sociedad Argentina de Investigación en Neurociencias (SAN)

  Drosophila has provided a powerful genetic system to study the molecular basis of neurodegenerative diseases. So far most efforts have been directed towards the expression of mutated genes that are known to be involved in human disease. We hypothesize that altered levels of expression of genes relevant for neuronal function and homeostasis might render a defective behavior. Behavioral defects that become apparent in aged but not in young flies should uncover genes with a potential involvement in neurodegeneration.  To test this hypothesis we have carried out a miss-expression screen based on an automated behavioral assay to quantitatively assess circadian locomotor activity in young and aged Drosophila individuals. We have identified several loci that distinctively affect this behavior in older flies. One of the interesting candidates showing progressive arrhythmicity in the activity paradigm resulted in a GAL4-mediated reduction in the endogenous levels of enabled (ena). ena down-regulation not only triggered degeneration of retinal structures but also gave rise to progressive neuronal death in specific regions of the adult brain. Interestingly, axonal transport defects were associated to deregulated ENA levels, suggesting that axonal clogging could underlie the neurodegeneration observed in the adult brain. Given the increasing interest in understanding neurological disorders, progress in this model system is likely to have a broad impact, ultimately assisting in the dissection of relevant pathways to neurodegeneration in the mammalian brain.