Yeast model for Parkinson’s

Researchers believe the PARK9 gene, mutations in which are thought to be responsible for some forms of hereditary Parkinson’s disease, has a role in protecting neurons from manganese toxicity and in rescuing neurons from alpha-synuclein over-expression, which is thought to cause both sporadic and familial Parkinson’s.

An international team of researchers, including Dr Antony Cooper and Dr Kathryn Hill from the Garvan Institute in Sydney, has used yeast as a model to study the complex interactions between genes linked to both sporadic and familial Parkinson’s disease as well as the role of manganese in Parkinson’s pathogenesis.

The team previously identified a set of genes that are potent modifiers of alpha-synuclein toxicity in yeast, published in Science in 2006. Alpha-syn is thought to normally act as a molecular chaperone but is also the main protein forming Lewy bodies, misfolded clumps of protein that are the prime markers of parkinsonism.

Using yeast, the team identified a gene called Ypt1 and its mammalian orthologue, Rab1, that could prevent the loss of dopaminergic neurons characteristic of Parkinson’s.

Now they have expanded their yeast screen and found that the yeast orthologue of PARK1, which they have named YPK9, for Yeast ParK9, rescues dopaminergic neuron loss when co-expressed with alpha-syn.

Further evidence that PARK9 has a protective role against alpha-syn over-expression was found in the C. elegans orthologue of PARK9, which when knocked down enhances alpha-syn misfolding.

When Ypt1 and Ypk9 were over-expressed together, there was also suppression of alpha-syn toxicity. This suggests that the interaction between the two is synergistic, the researchers say.

Mutations in PARK9 have been linked to hereditary Parkinson’s, but there is also a notable expression of PARK9 in surviving neurons in patients with sporadic Parkinson’s. The YPK9 study has now led the researchers to believe that a deficit in PARK9 function leads to disease, perhaps as it is then unable to counter alpha-syn toxicity.

They have also found a strong link between PARK9 and manganese toxicity. Manganese has been linked to environmental causes of Parkinson’s: case studies have shown that welders exposed to high manganese levels can suffer from a range of symptoms, termed manganism, of which parkinsonian-like symptoms is one.

While PARK9’s exact function is not known, it is generally thought to be a transmembrane cationic metal transporter, pumping cations across the cell. The team’s yeast studies have shown that cells with the yeast orthologue knocked down are very sensitive to manganese, leading them to suppose that PARK9 is probably a pump that protects cells from excess manganese.

Finally, the yeast screens have identified other modifiers of alpha-syn toxicity, including genes encoding a ubiquitin ligase, a ubiquitin protease and several kinases.

The research was published online in advance in Nature Genetics and is on the cover of the current issue.