Insights into ALS pathomechanisms: from flies to humans

Abstract

Amyotrophic Lateral Sclerosis (ALS) is a devastating neurodegenerative disease causing the death of motor neurons with consequent muscle atrophy and paralysis. Several neurodegenerative diseases have been modeled in Drosophila and genetic studies on this model organism led to the elucidation of crucial aspects of disease mechanisms. ALS, however, has lagged somewhat behind possibly because of the lack of a suitable genetic model. We were the first to develop a fly model for ALS and over the last few years, we have implemented and used this model for a large scale, unbiased modifier screen. We also report an extensive bioinformatic analysis of the genetic modifiers and we show that most of them are associated in a network of interacting genes controlling known as well as novel cellular processes involved in ALS pathogenesis. A similar analysis for the human homologues of the Drosophila modifiers and the validation of a subset of them in human tissues confirm and expand the significance of the data for the human disease. Finally, we analyze a possible application of the model in the process of therapeutic discovery in ALS and we discuss the importance of novel “non-obvious” models for the disease.

Keywords:

• Amyotrophic Lateral Sclerosis
• cell proliferation/apoptosis
• computational analysis
• Drosophila model
• endocytosis
• human tissue validation
• large scale modifier screen
• lipid droplets
• VAMP-Associated Protein B

Disclosure of Potential Conflicts of Interest

No potential conflicts of interest were disclosed.

Acknowledgments

We thank Margarete Heck for sharing with our lab the DrosoDel collection and the Bloomington Drosophila Stock Center for fly stocks. We are grateful to Steven Mitchell for help with scanning electron microscopy experiments.

Funding

This research was supported by the Wellcome Trust research grant (Pennetta8920), by a Motor Neurone Disease Association fellowship (Pennetta6231) and by an MND Scotland Association fellowship (Pennetta4085). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.