Neuron-glia Trans Signaling Intervention Mediates Neurotoxicity In Parkinson’s Model

A new framework for understanding the pathology of Parkinson’s disease is provided by research from the Buck Institute for Research on Aging.

Working in two fruit fly models of Parkinson’s, researchers at the Buck Institute elucidated a novel molecular mechanism that orchestrates a harmful cascade of inflammatory signaling and demonstrated that its disruption protects neurons as they age. The finding 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. 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,”

said Buck professor Pejmun Haghighi, Ph.D., senior author of the study.

Inflammatory Signaling Cascade

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.

LRRK2 Overexpression Enhances Fur1 Translation in DA Neurons

LRRK2 Overexpression Enhances Fur1 Translation in DA Neurons
Credit: Elie Maksoud et al CC-BY

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 pro-protein convertase, in dopaminergic neurons as the initiator of an inflammatory signaling cascade in glial cells.

Knockdown Of Furin1

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.

“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. 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,”

said postdoctoral fellow Elie Maksoud, Ph.D., the lead scientist on the study.

“We’re looking at a new way to prevent Parkinson’s, especially in those who have risk factors for the disease,” said Haghighi. “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. This study was supported by an NIH grant and by Buck Institute funding.

Elie Maksoud, Edward H. Liao, A. Pejmun Haghighi
A Neuron-Glial Trans-Signaling Cascade Mediates LRRK2-Induced Neurodegeneration
Cell Reports (2019) DOI: 10.1016/j.celrep.2019.01.077

Top Image: Simon Beggs, Wellcome Images