Loss of dopaminergic neurons is a hallmark of Parkinson's disease pathology. When dopaminergic neurons are stressed, they send out a call for help to nearby glial cells that are tasked with providing neuronal support, protection and nourishment. Under particular molecular conditions, those calls for help can over-activate the glial cells, resulting in a cascade of inflammatory signaling that eventually contributes to the degradation of these neurons over time.
Working in two fruit fly models of Parkinson's disease, researchers have characterized a novel molecular mechanism that orchestrates such a harmful cascade of inflammatory signaling and demonstrated that its disruption protects neurons as they age. The research, published in Cell Reports, provides a new framework for understanding the pathology of Parkinson's disease and offers an alternative approach for developing preventative treatments for a neurodegenerative disorder that afflicts millions of patients worldwide.
"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," said the senior author of the study. "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."
To induce Parkinson's-like neuronal defects, multiple sets of experiments were performed on flies that were genetically engineered to carry Parkinson's disease-related human genes or others that were exposed to a pesticide known as paraquat. In both cases, researchers identified Furin 1, a catalytic protein, in dopaminergic neurons as the initiator of an inflammatory signaling cascade in glial cells. Blocking this inflammatory signaling in the glial cells in both models of the disease reduced the toxic cross-talk and ultimately protected the neurons from degeneration.
Transgenic knockdown of Furin1 or its substrate the bone morphogenic protein (BMP) ligand glass bottom boat (Gbb) protects against LRRK2-induced loss of DA neurons. LRRK2 enhances the accumulation of phosphorylated Mad (pMad) in the nuclei of glial cells in the vicinity of DA neurons but not in DA neurons.
Consistently,exposure to paraquat enhances Furin 1 levels in DA neurons and induces BMP signaling in glia. In support of a neuron-glial signaling model, knocking down BMP pathway members only in glia, but not in neurons, can protect against paraquat toxicity.
"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 the lead scientist on the study. "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."
"We're looking at a new way to prevent Parkinson's, especially in those who have risk factors for the disease," said the senior author. "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." The researchers plan to use human cell culture models to further test the validity of the interactions.
Neural-glial cross talk implicated in Parkinson's
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