RESEARCH: New model for neurodegenerative disease

[Guest guest]

Perhaps this is part of the fruitfly genetic research alluded to at the MSA

Boston Conference as holding some promise.

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New model for neurodegenerative disease

It's amazing how many secrets one fly's brain can hold, Depraetere

discovers.

2 November 2000

VALERIE DEPRAETERE

Researchers have used the fruit fly Drosophila melanogaster to identify the

key proteins involved in the untreatable hereditary neurodegenerative

disease, spinocerebellar ataxia type 1 (SCA1), which affects a couple of

people in every 100,000.

SCA1, a condition from the same family as Huntington's disease, is caused by

mutations in the gene (called ataxin-1) that encodes the protein ataxin-1.

Sufferers develop problems with their gait, speech and eyesight in middle

age and become progressively more disabled from then on.

Botas, Huda Y. Zoghbi and their colleagues at the Baylor College of

Medicine, Houston, Texas, have made a new fruitfly model of SCA1 that paves

the way for the development of new therapeutic strategies1.

Botas and co-workers engineered fruitflies that make either the normal human

ataxin-1 protein, or the mutated, SCA1 form of the protein, in their nervous

systems. High levels of both forms of the protein induced neurodegeneration

as the insects aged. But more neural cells died in the flies expressing the

mutant protein.

The researchers then used their model system to identify new players in the

neurodegeneration that characterizes SCA1. They crossed their transgenic

flies with thousands of different fly strains, each bearing a different

mutation. They then looked at which progeny had more or less

neurodegeneration than normal.

" This [screen] allows identification of new players which weren't expected a

priori to affect neurodegeneration, " explains Sam Sisodia at University of

Chicago, Illinois, who works on neurodegenerative diseases such as

Alzheimer's.

The genes identified in this screen fall into four categories: First, Botas'

group found that mutations in genes that regulate protein folding or the

clear-up of misfolded proteins worsen neurodegeneration. Both types of

mutation increase levels of useless, misfolded proteins that ultimately

damage the brain.

Second, the screen revealed that a protein, 'glutathione-S-transferase',

known to be involved in detoxifying cells suffering from stress, also seems

to protect the brain against degeneration.

Third, mutations in the gene nucleoporin-44A suppress neurotoxicity. This

gene probably regulates the accumulation of ataxin-1 in cell nucleii,

suggesting that interfering with this process could be a way to reduce

neurodegeneration.

Fourth, the screen pointed the finger at mutations in genes encoding

proteins that are involved in the regulation of gene expression.

But, as Sisodia points out, " the question remains: how do all the players

identified in this screen fit together? " Botas, Zoghbi and their colleagues

are now " actively trying to rationalize how accumulation of misfolded

proteins can lead to altered gene and protein expression. "

References

Fernandez-Funez, P. et al. A genetic screen in Drosophila identifies novel

suppressors and enhancers of polyglutamine-induced neurodegeneration. Nature

408, 101 - 106 (2000).