A fruitful endeavor: Modeling ALS in the fruit fly

Abstract

For over a century Drosophila melanogaster, commonly known as the fruit fly, has been instrumental in genetics research and disease modeling. In more recent years, it has been a powerful tool for modeling and studying neurodegenerative diseases, including the devastating and fatal amyotrophic lateral sclerosis (ALS). The success of this model organism in ALS research comes from the availability of tools to manipulate gene/protein expression in a number of desired cell-types, and the subsequent recapitulation of cellular and molecular phenotypic features of the disease. Several Drosophila models have now been developed for studying the roles of ALS-associated genes in disease pathogenesis that allowed us to understand the molecular pathways that lead to motor neuron degeneration in ALS patients. Our primary goal in this review is to highlight the lessons we have learned using Drosophila models pertaining to ALS research.

The promises of neurodegenerative disease modeling

“…A brief overview only of the major results obtained in recent years with these models will be given here and the reader is referred to excellent recent reviews for more detailed accounts on the progress made in modelling specific diseases [4][5][6][7][8][9][10][11][12][13][14][15][16][17][18].…”

Neurodegeneration: A Leg Up on TDP-43

“…Several models of neurodegeneration have been developed with overexpression of disease proteins in the fly eye, given the ease of observing its structural degenerative phenotypes. Many studies have shown that overexpression of human TDP-43 in the fly eye results in an age-and dosedependent degeneration [5]. Reduction or overexpression of dTDP-43 in all fly neurons or within larval or adult motor neurons, the relevant cell type for ALS patients, results in decreased locomotion and adult lifespan [5].…”

“…Many studies have shown that overexpression of human TDP-43 in the fly eye results in an age-and dosedependent degeneration [5]. Reduction or overexpression of dTDP-43 in all fly neurons or within larval or adult motor neurons, the relevant cell type for ALS patients, results in decreased locomotion and adult lifespan [5]. Several groups have reported disrupted synaptic morphology and defective synaptic transmission when TDP-43 levels are altered strictly within motor neurons, suggesting that endogenous TDP-43 may function to regulate synaptic physiology [5].…”

“…The fruit fly Drosophila melanogaster has been used extensively to model the effects of both loss of fly TDP-43 (dTDP-43), encoded by the gene TBPH, and overexpression of dTDP-43 or human TDP-43 in the fly (reviewed in [5]). Wellcharacterized driver lines have allowed for TDP-43 levels to be altered within specific, restricted types of cells.…”

ALSUntangled 45: Antiretrovirals

“…In a Drosophila model of ALS expressing human TDP-43 (hTDP-43) (46), the transgenic fruit flies have progressive neurological degeneration characterized by brain cell death, progressive motor impairment, and a substantially reduced lifespan (25,46). Using this model, one group found that hTDP-43 selectively expressed in the flies' glial cells, but not when selectively expressed in neurons, caused a Drosophila endogenous retrovirus similar to HERV type K, named gypsy, to be expressed in higher quantities.…”