NOS2 Exhibits Therapeutic Potential in Mouse Study
Researchers explore suppressing the nitric oxide synthase 2 enzyme in the brain
Suppressing the production of an enzyme called nitric oxide synthase 2 (NOS2) led to reductions in alpha-synuclein-related abnormalities and neuroinflammation in a mouse model of Parkinson’s disease, a new study reports.
“Our data indicate that NOS2 may be a therapeutic target for modulating [Parkinson’s disease] in the brain,” the researchers wrote.
The study, “Genetic deletion of nitric oxide synthase 2 ameliorates Parkinson’s disease pathology and neuroinflammation in a transgenic mouse model of synucleinopathy,” was published in Molecular Brain.
Nitric oxide is a signaling molecule that plays a range of roles, including coordinating cell development and in inflammation. NOS2 is one of the main enzymes responsible for regulating nitric oxide levels in the brain, where it is involved in “neurotransmission, neural development, and the immune defense response,” the researchers wrote.
Recent studies have suggested that altered activity of the NOS2 enzyme may play a role in the progression of Alzheimer’s disease, a neurodegenerative condition that, similarly to Parkinson’s, is associated with the accumulation of toxic protein clumps.
However, the role of this enzyme in Parkinson’s has not been investigated.
To learn more, scientists in South Korea evaluated the effects of genetically deleting nos2, the gene that provides the recipe for making NOS2, in a mouse model of Parkinson’s.
The model carried mutations in the gene that provides instructions to produce alpha-synuclein — the protein that forms toxic clumps in Parkinson’s that are thought to contribute to disease progression. Toxic effects caused by this protein are referred to as synucleinopathy.
Brain tissue analysis showed that the levels of toxic forms of alpha-synuclein were increased significantly in the mouse model relative to healthy mice, but generally normalized in those lacking NOS2.
NOS2-deficient mice also had less inflammatory activation microglia and astrocytes, brain cells whose abnormal activation is thought to contribute to neuroinflammation in Parkinson’s.
“These data suggest that deletion of nos2 diminishes [alpha-synuclein-stimulated] microglial and astrocyte activation and that NOS2 is required for [alpha-synuclein-mediated] neuroinflammation in the brain,” the researchers wrote.
The team then analyzed gene expression profiles in the mice’s brain tissue — that is, looking at which genes are more or less active. They identified more than 1,000 genes whose activity was significantly altered between mice with Parkinson’s-like disease and healthy mice, and between Parkinson’s-like mice with and without NOS2.
Notably, the activity of a group of genes involved in responses to neuroinflammation was strongly reduced in NOS2-deficient mice.
“Overall, our results suggest that NOS2 is a crucial regulator of the synucleinopathy and neuroinflammatory response associated with” Parkinson’s disease, the researchers concluded.
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