Fruit flies help pave way for new Parkinson’s treatments

Human and fruit fly data have helped identify genes that may be risk factors or treatment targets in Parkinson’s disease, a study suggests.

The findings add to understanding of the endolysosomal pathway (ELP), the cell system that recycles and clears molecular waste, which has been increasingly linked to the toxic protein build-up seen in the condition.

The study was co-authored by Juan Botas, of Baylor College of Medicine, with Justin Moore, a graduate student in the Botas lab, as first author.

Botas said: “We were particularly excited to find that manipulation of STAM1/2, INPP4A/B, and TMEM55A/B genes improved movement problems, reduced neurodegeneration and protected dopamine-producing neurons in flies. This finding is important because it shows there is a way to prevent the loss of neurons, which causes the disease.”

Parkinson’s is a neurological disorder in which certain brain cells become damaged and die.

Abnormal clumps of a protein called alpha-synuclein are a molecular hallmark of the condition, and these toxic protein clumps are thought to play a key role in driving the disease.

In healthy cells, misfolded or clumped proteins can be recycled through the ELP. There is growing evidence that the ELP does not work properly in Parkinson’s, contributing to the toxic build-up of alpha-synuclein clumps.

One challenge in studying the ELP in Parkinson’s is that when cells are exposed to clumped alpha-synuclein, they naturally change ELP activity as they try to remove the toxic protein.

In lab models, it is often difficult for researchers to separate ELP changes that contribute to the disease from those that may be useful as the cell tries to compensate.

To address this, the team combined computer-based analyses with experimental validation in living organisms.

They first analysed molecular data sets from people with Parkinson’s and from fruit fly models, looking for networks of genes within the ELP that are consistently dysregulated in the disease.

The researchers were specifically interested in identifying ELP genes that help regulate the accumulation or clearance of alpha-synuclein.

Moore said: “Strategies that modify the toxic accumulation of alpha synuclein in neurons represent promising therapeutic approaches, so we focused on identifying genes involved in the recycling and waste-disposal system that is perturbed in people with Parkinson’s disease.”

After identifying candidate genes, the researchers carried out experiments using a well-established fruit fly model of Parkinson’s.

The model is useful for neurological research because fruit fly nerves are very similar to human nerves, but grow and can be studied much faster than those of other lab organisms such as mice.

This allowed the researchers to test the effects of dozens of potential candidate genes.

The researchers noted: “These findings help bridge a key gap in understanding how [toxic alpha-synuclein] intersects with ELP dysfunction by distinguishing alterations that exacerbate disease from those that confer protection.”

Among the findings, the team found evidence that a specific part of the ELP, the ESCRT network, may help clear toxic alpha-synuclein.

In particular, increasing the activity of the fly version of an ESCRT gene, STAM1/2, reduced alpha-synuclein levels and eased neurological symptoms in the flies. By contrast, reducing the activity of this gene worsened the disease.

Similar effects were seen for the INPP4A/B and TMEM55A/B genes, which belong to a different part of the ELP called the phosphatidylinositol cycle subnetwork.

Other genes were linked with worse disease when more active, suggesting they may help drive dysfunction.

Botas said: “We were excited about the findings.

“We found that many genes in two networks involved in the recycling and waste-disposal system of neurons, the ESCRT and the phosphatidylinositol cycle networks, have changes that either worsen or mitigate Parkinson’s disease symptoms.”

The team said the genes identified might be promising therapeutic targets, though further validation is needed to assess their effects.

The scientists concluded: “Collectively, these findings provide new mechanistic insight into the contribution of ELP dysfunction to [Parkinson’s], nominate previously unrecognised therapeutic targets and risk factors, and illustrate a generalisable strategy for identifying interventions capable of reprogramming maladaptive ELP responses in neurodegeneration.”