Parkinson’s disease (PD) is the second most common neurodegenerative disease after Alzheimer’s disease, affecting more than 10 million people worldwide. The disorder is characterized by progressive loss of dopaminergic neurons in the substantia nigra region of the brain, and by the accumulation of α-synuclein-rich Lewy bodies. People with Parkinson’s disease may experience tremors, limb stiffness, gait and balance problems, and move slowly, for example, when buttoning a shirt or walking.
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 has now found that, in the fruit fly Drosophila melanogaster, it takes two mutant genes to drive neurodegeneration.
Humans and fruit flies have two copies of each gene in most cells, and the team found that flies without one copy of the Gba1b gene, a common and potent PD genetic risk factor, do not develop neurological problems. However, they demonstrated that neurodegeneration does occur when flies lack one 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. Experiments in the fruit flies also pointed to potential therapeutic strategies.
“We found that carrying one mutant copy of Gba1b and one mutant copy of anne drives a slow, progressive neurodegeneration in flies,” explained Mingxue Gu, PhD, a postdoctoral associate in the lab of Hugo Bellen, PhD, distinguished service professor of molecular and human genetics at Baylor and chair in neurogenetics in the Duncan NRI. “The flies developed movement problems, lost neurons and showed disruption in the communication between neurons and glia.”
The team’s research manuscript, “Two lysosomal genes ATP13A2 and GBA1 interact to drive neurodegeneration,” has been released ahead of final publication in the journal Molecular Neurodegeneration. Gu is first author, and Bellen senior and corresponding author.
Parkinson’s disease (PD) is a genetically complex disorder in which combinations of heterozygous risk variants may contribute to pathogenesis, the authors explained. “Many PD risk loci encode lysosomal genes, such as GBA1, a common and potent risk factor, conferring at least a 5-fold increase. However, the mechanisms of GBA1 penetrance remain poorly understood.”
Bellen added, “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. 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. “Genome-wide association studies (GWAS) have consistently identified lysosomal genes as significant PD risk loci, and variants in GBA1 have emerged as the strongest genetic risk factor that predisposes to PD,” the researchers further noted.
For their study 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. They found that combined heterozygous loss of anne and Gba1b resulted in progressive age dependent locomotor deficits, functional abnormalities, and cell loss.
A closer look at the process leading to neurodegeneration revealed that Gba1b and anne work on different cell types. They showed that Gba1b is expressed in glial cells, which support and protect neurons, while anne is expressed 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 noted. “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. “Our study reveals that partial loss of Gba1b in glia and anne in neurons synergistically disrupts lysosomal pH and neuron-glia GlcCer homeostasis, triggering neurodegeneration,” the team wrote in summary.
The flies developed movement problems, lost neurons, and showed signs similar to early Parkinson’s disease. “These findings highlight lysosomal acidification, sphingolipid clearance, and polyamine regulation as critical intervention points in digenic PD,” the researchers stated.”
The team’s work further pointed to therapeutic strategies, showing that treatment with ML SA1, a drug that improves lysosome function, restored lysosomes’ healthier activity, and myriocin, which reduces GlcCer production, lowered toxic buildup. “One important finding was that we found ways to help reduce the damage,” Bellen said.
The authors further reported, “Notably, enhancing lysosomal trafficking or blocking GlcCer production mitigates these neurodegenerative phenotypes, providing potential therapeutic insights … The neurodegenerative phenotypes are rescued by: ML-SA1, an agonist of the lysosomal TRPML1 channel that has been reported to promote lysosomal membrane trafficking; myriocin, a compound that inhibits GlcCer production; and DFMO, a drug which inhibits polyamine synthesis.”
Bellen said, “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.”