A functional misexpression screen uncovers a role for enabled in progressive neurodegeneration.
Drosophila is a well-established model to study the molecular basis of neurodegenerative diseases. We carried out a misexpression screen to identify genes involved in neurodegeneration examining locomotor behavior in young and aged flies. We hypothesized that a progressive loss of rhythmic activity could reveal novel genes involved in neurodegenerative mechanisms. One of the interesting candidates showing progressive arrhythmicity has reduced enabled (ena) levels. ena down-regulation gave rise to progressive vacuolization in specific regions of the adult brain. Abnormal staining of pre-synaptic markers such as cystein string protein (CSP) suggest that axonal transport could underlie the neurodegeneration observed in the mutant. Reduced ena levels correlated with increased apoptosis, which could be rescued in the presence of p35, a general Caspase inhibitor. Thus, this mutant recapitulates two important features of human neurodegenerative diseases, i.e., vulnerability of certain neuronal populations and progressive degeneration, offering a unique scenario in which to unravel the specific mechanisms in an easily tractable organism.
Laboratorio de Genética del Comportamiento, Fundación Instituto Leloir, Instituto de Investigaciones Bioquímicas-Buenos Aires (IIB-BA, CONICET), Buenos Aires, Argentina.
Carolina
C
Rezával
Jimena
J
Berni
Ezequiel Axel
EA
Gorostiza
Santiago
S
Werbajh
María Marta
MM
Fagilde
María Paz
MP
Fernández
Esteban J
EJ
Beckwith
Ezequiel J
EJ
Aranovich
Carmen A
CA
Sabio y García
María Fernanda
MF
Ceriani
D000375:Aging / Q000473:pathology; D000818:Animals; D017209:Apoptosis; D004268:DNA-Binding Proteins / Q000235:genetics; D004330:Drosophila / Q000235:genetics*; D029721:Drosophila Proteins / Q000235:genetics; D015870:Gene Expression; D009043:Motor Activity; D019636:Neurodegenerative Diseases / Q000235:genetics*
C069672:Csp protein, Drosophila; D004268:DNA-Binding Proteins; D029721:Drosophila Proteins; C092744:ENA-VASP proteins