Methods and compositions for the identification and treatment of neurodegenerative disorders

A method of screening for a molecule having activity against a neurodegenerative disorder, comprising:

• (a) contacting a first transgenic Drosophila which expresses ataxin-1 with expanded polyglutamine repeats in its central nervous system with said molecule;
• and
• (b) determining whether progressive neuronal degeneration in said transgenic Drosophila is less severe than progressive neuronal degeneration of a second Drosophila which expresses the ataxin-1 with expanded polyglutamine repeats in its central nervous system but wherein said second Drosophila was not contacted with said molecule;
• wherein a reduction in the progressive neuronal degeneration of the first Drosophila relative to a the second Drosophila is indicative that the molecule has activity against a neurodegenerative disorder.

A method of screening for a molecule having activity against a neurodegenerative disorder, comprising:

• (a) contacting a first transgenic Drosophila larva which expresses ataxin-1 with expanded polyglutamine repeats in its eye imaginal disc with said molecule, which expression results in a rough eye phenotype;
• and
• (b) determining whether the rough eye phenotype in a first adult Drosophila resulting from said first larva is less severe than the rough eye phenotype of a second adult Drosophila resulting from a second larva which expresses the ataxin-1 with expanded polyglutamine repeats in its eye imaginal disc but wherein said second larva was not contacted with said molecule;
• wherein a reduction in the rough eye phenotype of the first adult Drosophila relative to a the second adult Drosophila is indicative that the molecule has activity against a neurodegenerative disorder.

A method of screening for a molecule having activity against a vertebrate disease, comprising:

• (a) contacting a first transgenic Drosophila larva which expresses a vertebrate disease gene associated with said vertebrate disease in its central nervous system with said molecule, said expression of said vertebrate disease gene resulting in a behavioral disorder;
• and
• (b) determining whether the behavioral disorder in a first adult Drosophila resulting from said first larva is less severe than the behavioral disorder of a second adult Drosophila resulting from a second larva which expresses said vertebrate disease gene in its central nervous system but wherein said second larva was not contacted with said molecule;
• wherein a reduction in severity of the behavioral disorder of the first adult Drosophila relative to a the second adult Drosophila is indicative that the molecule has activity against the vertebrate disease.

A method of identifying a modifier gene of SCA-1, comprising:

• (a) generating a cross between a transgenic Drosophila whose somatic and germ cells comprise a transgene operatively linked to a promoter, wherein the transgene encodes ataxin-1 with expanded polyglutamine repeats, wherein the expression of said transgene in the nervous system results in progressive neural degeneration;
• and a second Drosophila suspected of having one or more mutations in its germ cells, to produce progeny;
• (b) determining whether the progeny of said cross have a modified phenotype associated with the ataxin-1 transgene, wherein a modification of the phenotype associated with the ataxin-1 transgene is indicative that the second Drosophila has a mutation in a modifier gene of SCA-1;
• and
• (c) identifying the gene responsible for the modified phenotype associated with associated with the ataxin-1 transgene;
• wherein the gene identified in step (c) is a modifier gene of SCA-1.

A method of identifying a modifier gene of SCA-1, comprising:

• (a) crossing a transgenic Drosophila whose somatic and germ cells comprise a transgene operatively linked to a promoter, wherein the transgene encodes ataxin-1 with expanded polyglutamine repeats, wherein the expression of said transgene in the nervous system results in progressive neural degeneration, with a mutagenized Drosophila to produce progeny;
• (b) determining whether the progeny of the cross of step (a) Drosophila have a modified phenotype associated with the ataxin-1 transgene, wherein a modification of the phenotype associated with the ataxin-1 transgene is indicative that the mutagenized Drosophila has a mutation in a modifier gene of SCA-1;
• and
• (c) identifying the gene responsible for the modified phenotype associated with associated with the ataxin-1 transgene;
• wherein the gene identified in step (c) is a modifier gene of SCA-1.

A method of diagnosing a predisposition to SCA-1 in an individual, comprising:

• (a) measuring the expression level of normal ataxin-1 in a sample from said individual;
• and
• (b) determining whether said expression level is higher than normal expression of ataxin-1,
• wherein a higher expression level of ataxin-1 is indicative of a predisposition to SCA-1.