Genetics: Why fruit flies make model humans

The use of Drosophila fruit flies as a model for human neurodegenerative disease has led to the insight that molecular chaperones, such as heat shock proteins, may play a common role in the development of these diseases, says the University of Pennsylvania's Assoc Prof Nancy Bonini, in Australia this week for the Genetics Society of Australia's annual conference in Melbourne.

The discovery may eventually lead to a new class of drugs to treat neurodegenerative diseases, including Parkinson's, Huntington's and Alzheimer's.

Bonini's lab has been using Drosophila to look at some of the proteins that play a key role in diseases such as the polyglutamine disease spinocerebellar ataxia type 3, a disease in the same class as Huntington's disease which is caused by an extended run of glutamine repeats in the SCA-3 gene resulting in the accumulation of the protein in neurons, and Parkinson's disease, in which expression of alpha-synuclein is correlated to the neurodegeneration of dopaminergic cells.

"These are late onset progressive neurodegenerative diseases that show specific neuronal loss and accumulation of protein -- this suggests some commonality of mechanism," Bonini told the audience during her plenary lecture at the conference.

Bonini's models rely on expressing the causative proteins in the eyes and brains of the flies. Expression of the normal human SCA-3 gene in the eye doesn't have any effect, but a mutant form of the gene with an expanded polyglutamine run causes a late onset, progressive degeneration of the eye and the appearance of nuclear inclusions typical of the disease.

According to Bonini, this suggests that the some of the features of the disease might be conserved in Drosophila.

But interestingly, molecular chaperones such as the heat shock protein Hsp70, key players in the stress response pathway, also appear to be involved. These proteins, which are thought to prevent aggregation or assist with refolding of misfolded proteins, are expressed in the brain at the same time as the nuclear inclusions appear. Bonini's lab has shown that over-expressing the human form of Hsp70 in the flies expressing the mutant SCA-3 gene suppresses the neurodegeneration of the eye.

"Hsp70 does stop aggregates from forming, but it probably modulates the solubility of these proteins," she said.

Now Bonini has extended this experimental approach to create other fly models for human neurodegenerative diseases, in particular Parkinson's disease. This disease is characterised by the accumulation of alpha-synuclein in Lewy bodies, an inclusion next to the nucleus of dopaminergic neurons. While the protein is not a polyglutamine protein, the mechanism appears to be similar.

In Bonini's model, expression of the human alpha-synuclein protein -- there is no Drosophila equivalent -- is directed to dopaminergic neurons, and again, Hsp70 appears to protect the neurons from the toxic effects of the protein.

The two models suggest that modulation of molecular chaperones involved in stress response pathways such as Hsp70 might have a mitigating effect on the progressive development of neurodegenerative diseases. In fact, Bonini said, certain polymorphisms of Hsp70 have been linked to Parkinson's disease.

Bonini is now following a couple of different approaches with her models. One is to look for other genes and proteins that have a modulating effect on the progression of the disease. The other is to manipulate the stress response pathways with drugs to augment the chaperone activity to try to protect the cells from neurodegeneration.

One such drug of interest to Bonini is geldanamycin, which when fed to the alpha-synuclein-expressing flies prevented the onset of neurodegeneration. The drug works by lowering the threshold required for activation of the stress response --essentially turning it on sooner.

"This type of drug might be a new approach for treating Parkinson's disease," Bonini said. "In these diseases, augmenting chaperone activity might be a beneficial approach."

Bonini says her approach to creating fly models of human disease can be applied to many different diseases, even if there is no equivalent gene in the fly. And it's not necessary to entirely recreate the disease in the model -- replication of aspects of the disease is enough.

"You look at the phenotype and find similarities that parallel human diseases," she said.

Bonini hopes eventually to be able to use her models to work at the interface of environmental and genetic influences of complex diseases like Parkinson's and Alzheimer's disease. The fly, she says, will allow researchers to focus in on particular mechanisms rapidly and even screen potential drugs for appropriate activity, before moving into more complex animal models.