Testing the protective effect of a candidate small molecule in a Drosophila model of Amyotrophic Lateral Sclerosis (ALS)

Amyotrophic Lateral Sclerosis is a fatal neurodegenerative disease affecting upper and lower motor neurons. Patients display progressive paralysis with death typically resulting from diaphragmatic failure. Considerable evidence points out for a significant, but nevertheless complex genetic contribution for both ALS forms, familial and sporadic. Hence, subsequent work has identified a broad set of mutated genes associated with ALS symptoms, including Fused in Sarcoma (FUS). Not surprisingly, current efforts to develop new treatments for ALS involve the identification of small molecules that counteract the cellular hallmarks of the pathology. Ample evidence suggests that small bioactive molecules such as polyphenols have protective effects in neurodegenerative disorders. In fact, many studies have been supporting the possibility of changing the progression of the neurodegeneration through diet. Our study had a two-fold objective: to characterize the neuronal and kinematic decay of a Drosophila model of ALS; to test the protective effect of a small molecule previously identified for its capability to improve cellular growth of a yeast model overexpressing FUS. Since Drosophila has a relatively complex nervous system and a stereotyped set of motor outputs, it represents a step forward in the validation of this promising small molecule. Consistent with previous transgenic models, the Drosophila model of ALS overexpressing human FUS alleles (wild type and R521C) exhibited locomotor deficits, impairment of the climbing ability, reduced reproduction and shortened life span, with the degree of severity of mutant FUS phenotypes more aggressive than the wild type form. Furthermore, a detailed analysis of the locomotor pattern of the flies modelling ALS, using the custom-made FlyWalker system, revealed that the motor phenotype of these flies is evident after 14 days of FUS wild type expression. In addition, FUS wild type transgenic flies exposed to 10 mM of the small molecule showed a significant increase in the survival rate. Collectively, we conclude that the Drosophila model captures important aspects of human FUS-based ALS, providing a useful tool to test the efficacy of bioactive molecules