We are all guilty of cursing at those pesky fruit flies that annoy us as they zip around the room just out of reach of being swatted. Rarely, it seems, do we think about the incredible genetic insight lying within the The set of all genetic material in a particular organism or ... of these microscopic menaces. Drosophila melanogaster (the species name for the fruit fly) is in fact an extensively studied and valuable model organism that has helped unravel mysteries of neurodegeneration. One such mystery was the genetic cause of Troyer syndrome – a hereditary spastic paraplegia caused by a mutation in the human spartin gene. This mutation induces degeneration of corticospinal tract axons, which causes mental retardation, muscle wasting, short stature, lower extremity spasticity, and overall movement problems.
In extensive research conducted by Nahm et al., it was discovered that spartin (the Drosophila homolog for the A sequence of nucleic acids that forms a unit of genetic inh... underlying Troyer syndrome) is responsible for regulating synaptic growth and neuronal survival. Spartin works presynaptically to inhibit bone morphogenetic protein (BMP). This is crucial because in Drosophila increases in BMP signaling causes age-dependent neurodegeneration that resembles hereditary spastic paraplegia, which manifests as difficulties with motor movement and the formation of vacuoles (lesions) in the brain.
The BMP retrograde signal glass bottom boat (Gbb) binds to the wishful thinking receptor (Wit) to activate protein complexes that move into the nucleus to alter transcription of the fragile X mental retardation gene. This Drosophila fragile X mental retardation protein (dFMRP) regulates Futsch, a microtubule adaptor protein that increases microtubule stability and suppresses overproliferation of synapses.
The research team very cleverly created a null mutation in the spartin gene to evaluate what the effects of reducing spartin levels were on Connections between neurons where a signal is passed from on... growth, neuronal survival and neurodegeneration. Decreasing spartin prevented the The process by which a presynaptic neuron makes the postsyna... of BMP and cause several problems for the Drosophila with this mutation, including difficulty moving, vacuoles in the brain, synaptic overgrowth, and neurodegeneration. In a counterintuitive finding they discovered that Spartin acted through the dFMRP-Futsch pathway to increase microtuble instability and delaying neurodegeneration. In an interesting turn of events, the researchers discovered that applying a microtubule-destabilizing drug called vinblastine also delayed neurodegeneration, which suggests a role for microtubule stability in Troyer Syndrome. Drosophila homologs for human proteins associated with neurodegenerative diseases provide mechanistic insight into what signaling pathways induce degeneration in hereditary spastic paraplegias and multiple sclerosis.
Nahm M., Lee M.J., Parkinson W., Lee M., Kim H., Kim Y.J., Kim S., Cho Y., Min B.M., Bae Y. & Broadie K. & (2013). Spartin Regulates Synaptic Growth and Neuronal Survival by Inhibiting BMP-Mediated Microtubule Stabilization, The functional unit of the nervous system, a nerve cell that..., 77 (4) 680-695. DOI: 10.1016/j.neuron.2012.12.015
Image adapted from National Institute of Genetics, Suzuki Group.