Fruit flies help identify genes that may be treatment targets in Parkinson’s

By analyzing data sets from both humans and fruit flies and conducting experiments in living fruit flies, researchers have identified several genes that may be risk factors or useful therapeutic targets in Parkinson’s disease, according to a study.

“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,” Juan Botas, PhD, co-author of the study at Baylor College of Medicine, said in a news story from the college.

The study, “Integration of cross-species multi-omics with in vivo experimental validation identifies Parkinson’s disease therapeutic targets and novel risk factors within endolysosomal pathway subnetworks,” was published in Neurobiology of Disease.

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Study combines analyses, experimental validation in living organisms

Parkinson’s is a neurological disorder in which certain brain cells sicken and die. Abnormal clumps of a protein called alpha-synuclein are a molecular hallmark of Parkinson’s, 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 endolysosomal pathway (ELP), which broadly refers to the molecular systems that cells use to discard molecular waste. There’s accumulating evidence that the ELP doesn’t function correctly in Parkinson’s, contributing to the toxic buildup of alpha-synuclein clumps.

But one of the tricky things about studying the ELP in Parkinson’s is that when cells are exposed to clumped alpha-synuclein, they will naturally change ELP activity as they try to get rid of the toxic protein. In lab models, it’s often very difficult for researchers to tease out which ELP changes contribute to the disease and which are potentially beneficial as the cell tries to compensate.

In this study, Botas and colleagues combined computer-based analyses with experimental validation in living organisms to address this issue. The researchers first analyzed molecular data sets from people with Parkinson’s and 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.

“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,” said Justin Moore, a graduate student in the Botas lab and first author of the study.

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Fruit fly nerves very similar to those of humans

After identifying candidate genes, the researchers conducted experiments using a well-established fruit fly model of Parkinson’s. This model is useful for neurological research because fruit fly nerves are very similar to human nerves, yet they grow and can be studied much faster than other lab organisms, such as mice. As such, this model allowed the researchers to experimentally test the effects of dozens of potential candidate genes.

“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,” the researchers noted.

Among the notable findings, the researchers found evidence that a specific part of the ELP, the ESCRT network, may help clear toxic alpha-synuclein. In particular, they found that increasing the activity of the fly version of an ESCRT gene, STAM1/2, reduced alpha-synuclein levels and alleviated neurological symptoms in the flies. By contrast, reducing the activity of this gene worsened the disease.

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

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

“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,” Botas said.

The researchers said that these genes might be promising therapeutic targets in Parkinson’s, though they stressed that further validation is needed to assess their effects.

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