"Role of insulin signaling in C. elegans models of Huntington disease"

BLANCO MG; RAYES D; ANDERSEN N; DE ROSA MJ; VEUTHEY T

Buenos Aires

Congreso; Reunión Conjunta de Sociedades de Biociencias; 2017

Sociedades de Biociencias

Insulin/insulin-like growth factor signaling (IIS) is an universal conserved pathway, with relevant functions in metabolism, growth,development and longevity. Reduced IIS has been shown to extend lifespan and elevate stress resistance in many animals. On the other hand, it has also been reported that an apparent increase of IIS protects against proteotoxicity. This contradiction leads to the intriguing question of the role of IIS pathway in the development of neurodegenerative diseases.To shed light into this, we use C. elegans models of Huntington disease (HD). These models express expanded polyglutamines(polyQ) repeats coupled to GFP that induce protein aggregation in muscular or neuronal cells, thus mimicking the aggregation that occurs in HD. Mutants of the mammalian insulin/IGF-1 receptor ortholog, DAF-2, were crossed with HD strains. As previously reported by other groups, we found that daf-2 mutants are long-lived and extremely resistant to oxidative stress. Unexpectedly, we found that daf-2 mutant worms expressing polyQ repeats have an increased number of aggregates and reduced mobility when compared with the control.Besides, the lifespan of daf-2 mutants expressing neuronal polyQ repeats is signifcantly shorter than control animals. Moreover, polyQ repeats severely impairs the oxidative stress resistance of daf-2 null mutants while it does not affect the resistance of wild-type strains.Taken together, the results reported here show that the inactivation of IIS results in an impairment of the proteostasis network. Further studies are required to elucidate the molecular mechanisms that explains this protective effect of IIS in the progression of HD. Given the conservation of the IIS throughout the animal kingdom, this study will contribute to the understanding of the insulin paradox (protective or harmful) in the context of neurodegenerative diseases.