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Gene hunting in the eye of the fly
New Drosophila model of spinocerebellar ataxia type 1
By Bijal P. Trivedi

A new fly model of the neurodegenerative disease spinocerebellar ataxia type 1 (SCA1) has enabled researchers to identify a collection of genes that may participate in causing the disease. The flies will be used to screen drug candidates for their ability to slow or halt disease progression.

"We know that a gene mutation produces the abnormal protein in SCA1, but what processes happen between the mutation and neuron death is a black box," says Juan Botas, of the Baylor College of Medicine in Houston, Texas. Botas' team created the fly models of SCA1 to discover which genes accelerate nerve cell loss, and which genes will prevent it. The expectation is that the genes involved in the fly model will be the same as in the human disease.

1. A normal healthy fly eye. 2. The eye of a fly carrying the toxic form of ataxin-1 [SCA1-82]. The eye surface is disorganized, rough and uneven. 3. A modifier gene discovered in the screen is able to partially suppress the effects of [SCA1-82] and almost rescue the eye. The researchers hope that this modifier gene may have the same effect in humans. View larger

SCA1 results from the buildup of an abnormally long ataxin-1 protein inside Perkinje cells in the cerebellum. These cells play an important role in controlling body movement and when they die, SCA1 patients loose body coordination and experience problems with speech and respiration.

The extended form of ataxin-1 is caused by a genetic mutation that adds a string of extra glutamine amino acids in the middle of the protein. The extra glutamines make the ataxin protein sticky and cause it to form toxic clumps that build up in the nucleus, killing the Perkinje cells. SCA1 and Huntington's disease are members of a family of disorders known as polyglutamine diseases, which are all caused by an insertion of glutamines into the normal protein.

The researchers created two types of flies; one carrying a normal human ataxin-1 gene, and one carrying an abnormal, extended form of the ataxin-1 gene that is known to cause disease in humans.

Pedro Fernandez-Funez and his colleagues at Baylor created breeds of flies that produce the normal and abnormal proteins in the fly eye. The fly eye is an extensively studied, very complex structure, which is exquisitely sensitive to genetic changes and thus particularly valuable for gene hunting. In a normal fly the eye has a smooth, red and glassy surface. All flies that carry the toxic form of ataxin-1 have a disorganized, rough and uneven eye surface. Genes that participate in the "black-box" stage of the diseases will modify the rough eye, either making it better or worse.

The researchers bred the rough-eyed SCA1 flies with a panel of mutant flies and screened the offspring for flies with either rougher or smoother eyes than the parent. The screen revealed 7 genes that prevented cell death and made the eyes smoother and 20 genes that made the eyes worse.

The Baylor team identified genes involved in protein folding and protein destruction, chaparones and Ubiquitin respectively, both of which had previously been tied to the SCA1. They also found categories of genes involved in other processes that were not known to affect neurodegeneration. Six genes produced transcription cofactors that switch genes on and off. Four genes produced binding proteins that affect how RNA is processed. One gene removed toxins from the cell. The work is reported in the current issue of Nature.

All the modifier genes will be tested to see whether they also play a role in Alzheimer's and Parkinson's disease. "If one gene is common to a group of these neurodegenerative diseases then it would prove they were all caused by the same molecular mechanism," says Fernandez-Funez.

"These flies are not just tools for picking up genes that affect the disease. They are also important pharmacological models for drug screening," says Botas.

The Baylor researchers plan to feed flies a battery of different compounds looking for those that slow or halt neuron death. The advantage to using flies is that many chemicals can be tested and high throughput screens can be completed quickly. Searching for drug candidates that prevent neurodegeneration by feeding flies different chemicals has never been tried before, says Fernandez-Funez. "We are very excited to begin."

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Fernandez-Funez, P. et al. Identification of genes that modify ataxin-1-induced neurodegeneration. Nature 408, 101-106 (November 2, 2000).

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