In a series of laboratory experiments, researchers tracked the role of the p62 protein, showing how its aberrant modification by nitric oxide (NO) leads to inhibition of autophagy, a cellular disposal process that "eats" dysfunctional proteins and organelles. The authors also show how that inhibition, in turn, causes build-up and then secretion of misfolded alpha-synuclein and other proteins that p62 would normally have marked for destruction.
The study fills in gaps in understanding of the mechanisms leading to autophagic dysfunction, which has long been thought to contribute to accumulation and spread of misshapen proteins, as well as synaptic disruption, seen in many neurological disorders, the authors note in the Journal of Neuroscience.
Buildup of misfolded proteins "like alpha-synuclein and other proteins (beta-amyloid, TDP-43, Tau, and others) were thought to contribute to neurological diseases including Parkinson's disease, Lewy body dementia, Alzheimer's disease, frontotemporal dementia and additional forms of dementia," said senior study author Dr. Stuart A. Lipton, a professor and founding director of the Neurodegeneration New Medicines Center at the Scripps Research Institute, in La Jolla, California,
"Moreover, in recent years, spread throughout the brain of these misfolded proteins was thought to underlie the progression of the disease to other brain regions," Dr. Lipton, who is also a clinical neurology attending physician with the University of California, San Diego Health System, told Reuters Health by email.
Dr. Lipton and colleagues had previously shown that build-up of misfolded or mutated proteins, including alpha-synuclein, or exposure to mitochondrial toxins like rotenone or paraquat, raises intracellular levels of reactive nitrogen species (RNS) and nitric oxide (NO). They also knew that excess RNS could cause aberrant chemical modification of proteins by S-nitrosylation.
"Protein S-nitrosylation is in some sense analogous to the action of protein phosphorylation, a much better known and characterized process for regulating protein function," Dr. Lipton noted.
The team theorized that p62 would be susceptible to this modification under conditions where RNS and NO are elevated. In the current study, they used dopaminergic neurons created from human induced pluripotent stem cells, as well as gene editing, PD/LBD-model mice, and postmortem human brain tissue to examine whether that happens and what it would mean.
The researchers showed that excess NO in neurons does cause S-nitrosylation of p62, turning the protein into dysfunctional SNO-p62. That leads to inhibition of autophagic flux, accumulation of misfolded alpha-synuclein, and synucleinopathy, they report.
"Moreover, the misfolded protein buildup then 'spills over' and spreads to other nerve cells and other cell types in the brain by being released into the extracellular space," Dr. Lipton explained.
"Since most scientists tend to perform experiments under room air, which represents a rather oxidizing condition, many scientists have missed these protein S-nitrosylation reactions because their proteins were already oxidized by the ambient air conditions," Dr. Lipton pointed out. "Hence, we have to study these reactions under controlled environments similar to those that occur in the brain and other organ systems in order to see and characterize the S-nitrosylation of the panoply of proteins that occurs."
Alpha-synuclein is the primary component of Lewy bodies, the study authors note in their report, and SNO-p62 is also greatly elevated in human LBD patient brains. The current study shows that "pathological protein S-nitrosylation of p62 represents a critical factor not only for autophagic inhibition and demise of individual neurons, but also for alpha-syn release and spread of disease throughout the nervous system," they conclude.
"Such aberrant S-nitrosylation reactions triggered by environmental toxins, such as air pollution and other factors, may trigger the buildup of RNS and thus contribute to many aberrant S-nitrosylation reactions on a variety of protein networks," Dr. Lipton said. Last year, his group published a study linking one such network of aberrant nitrosylation reactions to synaptic damage that contributes to memory loss in Alzheimer's disease, he noted.
"These reactions, we believe, are very common and previously were not known. The discovery of aberrant protein S-nitrosylation on p62 is the latest example of these pathogenic chemical redox reactions, and many more will be appearing in the coming months - they represent major factors in the pathogenesis of both neurodevelopmental and neurodegenerative diseases because we humans are particularly susceptible to this kind of redox chemical injury at the extremes of life," Dr. Lipton added.
Since S-nitrosylation of some proteins is a normal signaling mechanism, however, simply decreasing the generation of RNS/NO would not work therapeutically in most instances, Dr. Lipton said. Instead, his group is developing methods to target particular pathways to aberrant S-nitrosylation of a specific protein. "In some cases, we can even prevent a specific nitrosylation event on a protein by providing a mimic protein or other targeted chemical intervention," Dr. Lipton said.
The study received funding from the National Institutes of Health, the Brain & Behavior Research Foundation, and the Michael J. Fox Foundation for Parkinson's Research.
SOURCE: https://bit.ly/3hIxO2M Journal of Neuroscience, online February 15, 2022.
By Christine Soares
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