A novel strategy that combines computational and experimental approaches has allowed researchers at Baylor College of Medicine and the Duncan Neurological Research Institute (Duncan NRI) at Texas Children's Hospital to distinguish alterations in gene function that contribute to Parkinson's disease from those that protect from the condition.
The study, published in Neurobiology of Disease , revealed novel risk factors and previously unrecognized therapeutic targets, offering hope for a future in which effective therapies will be available to prevent, slow down or stop this devastating disease.
"Parkinson's disease is the most common neurodegenerative movement disorder – it affects more than 10 million people worldwide," said corresponding author Dr. Juan Botas , professor of molecular and human genetics and molecular and cellular biology at Baylor. Botas also is a member of the Duncan NRI and director of the High Throughput Behavioral Screening Core at Texas Children's. "People with the condition have tremors, muscle stiffness and balance problems. They move slowly with a shuffling gait; their symptoms often start gradually and worsen over the years. Current therapies only relieve symptoms but do not prevent the gradual loss of brain cells called neurons that causes the disease."
A defining feature of Parkinson's disease is the buildup of a protein called alpha synuclein inside neurons. In healthy cells, alpha synuclein is continuously made, used, recycled and broken down. In Parkinson's disease, this recycling and waste-disposal process goes wrong and alpha synuclein accumulates, clumps together, and becomes toxic, particularly to dopamine-producing neurons that are essential for normal movement.
"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 first author Justin Moore , graduate student in the program of Quantitative and Computational Biosciences working in the Botas lab. "We knew that not all gene function changes may have the same effect. Some changes may contribute to disease, others may be the cell's attempt to defend itself and some changes may not have an effect."
Distinguishing harmful changes from helpful and neutral ones is essential to design effective therapies. Identifying gene function changes that promote disease could lead to strategies to counteract their negative effects, while finding gene changes that protect from the disease could result in therapies that enhance the beneficial effects.
First, the researchers used computational methods to combine different types of large-scale data – including genetics, gene expression and protein measurements – from people and model organisms to identify networks of genes that work together and are consistently altered in Parkinson's disease. To determine whether these gene groups influenced disease, the team tested them in a well-established fruit fly model of Parkinson's disease. In this model, flies produce human alpha synuclein in their neurons, which causes progressive movement problems and loss of dopamine neurons – features that closely resemble aspects of human Parkinson's disease.
"We were excited about the findings," Botas said. "Notably, 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. 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."
Altogether, the study provides a better understanding of how Parkinson's disease happens by distinguishing between alterations in gene function that promote the disease from those that provide protection. These findings point at new risk factors and potential therapeutic targets and show in an animal model that it is possible to change the course of the disease by reprogramming the recycling and waste-disposal system of neurons.
Justin Moore performed most of the work, Leo Rao, Sara Garcia-Bellido, Fangfei Guo and Jorge Botas, all at Baylor College of Medicine and the Duncan NRI, also contributed to this project.
This work was funded by the Huffington Foundation, NIH/NIA U0 1AG072439 and NIH/NIA U01 AG068214.
