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
