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 genomeThe set of all genetic material in a particular organism or ... More 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.

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Fluorescence microscope image of a drosophila fly brain.

In extensive research conducted by Nahm et al., it was discovered that spartin (the Drosophila homolog for the geneA sequence of nucleic acids that forms a unit of genetic inh... More 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.

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The research team very cleverly created a null mutation in the spartin gene to evaluate what the effects of reducing spartin levels were on synapseConnections between neurons where a signal is passed from on... More growth, neuronal survival and neurodegeneration.  Decreasing spartin prevented the inhibitionThe process by which a presynaptic neuron makes the postsyna... More 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.

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References:

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, Neuron, 77 (4) 680-695. DOI: 

Image adapted from National Institute of Genetics, Suzuki Group.

Jillian L. Shaw

Jillian decided to dedicate herself to a life of exploring the mysteries of the brain after reading neurological case studies by Oliver Sachs and Ramachandran as a student at Vassar College.After completing a B.A. in Neuroscience with honors in 2009, Jillian headed to USC to pursue a Ph.D. in Neuroscience where she is now in her 5th year.A research stint in Belgium exposed Jillian to the complexities of cell signaling pathways, and her interests shifted from cognitive neuroscience to cellular and molecular neuroscience.Her current research focuses on the link between Down syndrome and Alzheimer’s disease using Drosophila as a genetic model to explore axonal transport, mitochondria dysfunction, synaptic defects, and neurodegeneration.When she is not in the lab, Jillian is forming new synapses by rock climbing throughout Southern California.

Jillian L. Shaw

View posts by Jillian L. Shaw
Jillian decided to dedicate herself to a life of exploring the mysteries of the brain after reading neurological case studies by Oliver Sachs and Ramachandran as a student at Vassar College. After completing a B.A. in Neuroscience with honors in 2009, Jillian headed to USC to pursue a Ph.D. in Neuroscience where she is now in her 5th year. A research stint in Belgium exposed Jillian to the complexities of cell signaling pathways, and her interests shifted from cognitive neuroscience to cellular and molecular neuroscience. Her current research focuses on the link between Down syndrome and Alzheimer’s disease using Drosophila as a genetic model to explore axonal transport, mitochondria dysfunction, synaptic defects, and neurodegeneration. When she is not in the lab, Jillian is forming new synapses by rock climbing throughout Southern California.

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