Parkinson's disease (PD) is the second most common neurodegenerative disease after Alzheimer's disease, affecting more than 10 million people worldwide. People with this condition may experience tremors, limb stiffness, gait and balance problems and move slowly, like when buttoning a shirt or walking. These symptoms happen because certain brain cells die over time. Although scientists have known some of the factors that raise a person's risk, the question remains of why some people with genetic risk factors develop the disease while others never do.
A team at Baylor College of Medicine, the Duncan Neurological Research Institute (Duncan NRI) at Texas Children's Hospital and collaborating institutions found in the laboratory fruit fly that it takes two mutant genes to drive neurodegeneration. People and fruit flies have two copies of each gene in most cells. Flies without one copy of the Gba1b gene, a common and potent PD genetic risk factor, do not develop neurological problems. However, neurodegeneration occurs when flies lack both a copy of Gba1b and one copy of anne (the fruit fly equivalent of the human gene ATP13A2). Importantly, the researchers identified multiple PD individuals carrying ATP13A2 and GBA1 variants. The study appeared in Molecular Neurodegeneration.
"We knew from human studies that people carrying one copy of mutant GBA1 and one copy of normal GBA1 gene have a 5-fold increase in the risk of developing PD, but do not always develop the condition," said corresponding author Dr. Hugo Bellen , Distinguished Service Professor of molecular and human genetics at Baylor and chair in neurogenetics in the Duncan NRI. "A second factor must be in place for the condition to arise."
The researchers looked for the second factor among genes linked to lysosomes, structures inside cells responsible for breaking down and recycling cellular material, because many PD risk genes like GBA1 also are linked to lysosomes. The team worked with fruit flies to examine how the Gba1b mutant gene interacts with dozens of other genes involved in lysosome function. Their goal was to find out whether Gba1b drives neurodegeneration when paired with other lysosomal genes.
"We found that carrying one mutant copy of Gba1b and one mutant copy of anne drives a slow, progressive neurodegeneration in flies. The flies developed movement problems, lost neurons and showed disruption in the communication between neurons and glia," said first author Dr. Mingxue Gu , a postdoctoral associate in the Bellen lab.
A closer look at the process leading to neurodegeneration revealed that Gba1b and anne work on different cell types. Gba1b works mainly in glial cells, which support and protect neurons, and anne works mostly in neurons, which send electric signals that sustain neural networks. But how can problems in two different cell types lead to neurodegeneration?
"One surprising result was that the earliest signs of damage didn't appear in neurons but in glial cells," Gu said. "These cells began swelling, detaching from nearby neurons, and showing signs of distress. We tied this to accumulation of a fat molecule called glucosylceramide (GlcCer) in glial lysosomes."
In flies also carrying a mutant anne, lysosomes in the neurons failed to maintain proper acidity. This caused neurons to produce excess GlcCer, which was then transferred to glial cells in amounts far beyond what glia can handle. It's like having a recycling center (the glia) that's already short staffed, suddenly being overwhelmed with extra garbage arriving from the neighborhood (the neurons).
As a result, waste materials piled up in glial cells, leading to swelling and structural damage. Without healthy glia to support and protect them, neurons eventually failed, especially those involved in vision and movement. The flies developed movement problems, lost neurons, and showed signs similar to early Parkinson's disease.
"One important finding was that we found ways to help reduce the damage," Bellen said.
Treatment with ML SA1, a drug that improves lysosome function, restored lysosomes' healthier activity, and myriocin, which reduces GlcCer production, lowered toxic buildup. "These treatments don't point to an immediate cure for Parkinson's, but they reveal promising biological pathways that could be explored in future therapies," Bellen said.
Other contributors to this work include Jinghan Zhao, Mingxi Deng, Guang Lin, Xueyang Pan, Wenwen Lin, Mengqi Ma, Jinyong Kim, Seul Kee Byeon, Akhilesh Pandey, Lara M. Lange, Chad A. Shaw, Jonggeol Kim, Joanne Trinh, Christine Klein, Oguz Kanca and Joshua M. Shulman. The authors are affiliated with one or more of the following institutions: Baylor College of Medicine, Duncan NRI, Mayo Clinic, Anipal Academy of Higher Education – India, University of Luebeck – Germany and National Institute of Aging.
This study was supported by the Huffington Foundation, the Duncan NRI, NIH grants U01CA271410 and 1468 P30CA15083, and DBT/ Wellcome Trust India Alliance (grant IA/CRC/20/1/600002). Further support was provided by the Intramural Research Program of the National Institute on Aging, National Institutes of Health, Department of Health and Human Services (grants ZO1 AG000535 and ZIA AG000949), the Silverstein Foundation for PD with GBA1 and a National Institute of Child Health & Human Development grant (U54 HD083092).
