The protein Furin 1, produced by dopaminergic neurons — nerve cells that synthesize the neurotransmitter dopamine — triggers a harmful inflammatory molecular cascade in neighboring non-neuronal cells that contributes to the degradation of these neurons over time, a study in flies found.
Because Furin 1 is controlled by LRRK2 — a major player in neurodegeneration in Parkinson’s disease — the findings begin to reveal how LRRK2 causes the loss of dopaminergic neurons in patients. Blocking this inflammatory signaling protected flies from age-dependent neurodegeneration.
The research, “A Neuron-Glial Trans-Signaling Cascade Mediates LRRK2-Induced Neurodegeneration,” was published in Cell Reports.
Mutations in the LRRK2 gene are one of the most commonly known genetic causes of Parkinson’s disease and usually result in the malfunctioning of lysosomes — special compartments within cells that digest and recycle different types of molecules. Lysosomal dysfunction is involved in the formation of Lewy body protein aggregates and, therefore, neurodegeneration.
Glial cells — non-neuronal cells that provide support, protection, and nutrition for neurons — help neurons when they are in molecular distress. In certain conditions, glia become overly activated by these “mayday” callings and activate an inflammatory cascade, which contributes to the degradation of the distressed neurons.
Researchers from the Buck Institute for Research on Aging have previously identified Furin 1 as a mediator of LRRK2’s ability to regulate neuronal transmission in Drosophila melanogaster (fruit fly) larvae.
“Working in flies allowed us to identify a vicious cycle: stressed neurons signal to the glia and trigger inflammatory signals in the glia, which become harmful for the neuron as the brain ages. Interestingly, the genetic components of this crosstalk are conserved between flies and humans, boosting our enthusiasm and confidence that future work might lead to novel therapeutic paradigms,” Buck professor Pejmun Haghighi, PhD, senior author of the study, said in a news release.
In this study, investigators sought to test whether Furin 1 responds to LRRK2 in the adult fly brain and whether it is involved in mediating the toxic effect of LRRK2 mutations in dopamine-producing neurons.
The team generated two Parkinson’s disease fly models: one produced too much LRRK2 within neurons; the other had paraquat-induced dopaminergic neurodegeneration.
Paraquat is a toxic, fast-acting herbicide that when fed to flies induces the rapid degradation of dopamine-producing neurons and severely reduces their lifespan.
Fly brain tissue analysis revealed both LRRK2 overexpression and paraquat models had increased Furin 1 protein production in dopaminergic neurons. Furin 1 was found to be regulated by LRRK2 and the trigger of the inflammatory molecular cascade.
“Furin 1 is the real culprit in the interaction between the neurons and glial cells. It’s the ‘finger’ that pushes the switch on the signaling cascade,” said postdoctoral fellow Elie Maksoud, PhD, the study’s lead author.
Furthermore, reducing the amount of Furin 1 within neurons protected against toxicity.
Furin 1 acts on a molecule known as glass bottom boat (Gbb). Gbb binds to bone morphogenetic proteins (BMPs), a family of proteins that promote the formation of bone and the skeleton but are also essential for several neuronal processes. Various forms of these BMPs can be found in the form of molecular receptors in glial cells.
Scientists set up to investigate whether there was a genetic interaction between the overexpression of LRRK2 or Furin 1 and genes associated with BMP molecular pathways.
They reported that furin 1 toxicity was linked to increased BMP signaling in glial cells of both fruit fly models. By genetically silencing Gbb (reducing its production), researchers demonstrated that the action reversed the age-dependent loss of dopaminergic neurons and protected against LRRK2 protein toxicity.
Results suggest that the observed toxicity is mostly initiated by dopamine-producing neurons, which in turn activate BMP-mediated molecular communication with glial cells.
Investigators hypothesize that these supportive non-neuronal cells might send inflammatory signals back to neurons, causing neurodegeneration.
“Furin 1 is a druggable target. Our hope is that treatments can be developed to reduce this toxic crosstalk before it becomes a serious problem for the dopaminergic neurons,” Maksoud said.
Haghighi said, “We have known for some time that different forms of genetic or environmental stress in neurons can trigger a response in glial cells; now we’ve been able to identify a molecular mechanism that explains how neuronal stress can lead to activation of inflammatory signals in glial cells.
“We’re looking at a new way to prevent Parkinson’s, especially in those who have risk factors for the disease. The effects of this toxic signaling are age-dependent, they accumulate over time. The goal is to intervene as early in the disease process as possible.”