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Genetic deletion of nitric oxide synthase 2 ameliorates Parkinson's disease pathology and neuroinflammation in a transgenic mouse model of synucleinopathy.

ABSTRACT: Studies of mouse models of Alzheimer's disease (AD) have demonstrated that nitric oxide synthase 2 (NOS2) is involved in AD pathology. However, the effects of NOS2 on the pathology of Parkinson's disease (PD) are not well studied. To address this gap, we examined the impact of NOS2 on disease-associated phenotypes in a mouse model of PD. Transgenic mice carrying the A53T mutation of α-synuclein (Syn^A53T) and newly generated double transgenic mice with deletion of NOS2 (Syn^A53T/NOS2^-/-) were used. Compared with Syn^A53T mice, the loss of nos2 decreased α-synuclein phosphorylation at serine 129 and reduced α-synuclein-induced microglial and astrocyte activation in Syn^A53T/NOS^-/- mice. Additionally, neuroinflammation-related gene clusters in the deep mesencephalic nucleus (DpMe) were altered in Syn^A53T/NOS^-/- mice compared with Syn^A53T mice. Taken together, our results suggest that deletion of nos2 alleviates α-synuclein pathology and α-synuclein-associated neuroinflammatory responses in the brain.

SUBMITTER: Kim J

PROVIDER: S-EPMC9841612 | biostudies-literature | 2023 Jan

REPOSITORIES: biostudies-literature

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Genetic deletion of nitric oxide synthase 2 ameliorates Parkinson's disease pathology and neuroinflammation in a transgenic mouse model of synucleinopathy.

Kim Jieun J Han Jung-Youn JY Lee Yujeong Y Kim Kipom K Choi Young Pyo YP Chae Sehyun S Hoe Hyang-Sook HS

Molecular brain 20230116 1

Studies of mouse models of Alzheimer's disease (AD) have demonstrated that nitric oxide synthase 2 (NOS2) is involved in AD pathology. However, the effects of NOS2 on the pathology of Parkinson's disease (PD) are not well studied. To address this gap, we examined the impact of NOS2 on disease-associated phenotypes in a mouse model of PD. Transgenic mice carrying the A53T mutation of α-synuclein (Syn<sup>A53T</sup>) and newly generated double transgenic mice with deletion of NOS2 (Syn<sup>A53T</s ...[more]

PMID: 36647152

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Project description:The cellular deformability of red blood cells (RBC) is exceptional among mammalian cells and facilitates nutrient delivery throughout the microcirculation; however, this physical property is negatively impacted by oxidative stress. It remains unresolved whether the molecular determinants of cellular deformability - which in the contemporary model of RBC are increasingly recognized - are sensitive to free radicals. Moreover, given cellular deformability has recently been demonstrated to increase following exposure to specific doses of mechanical stimulation, the potential for using shear "conditioning" as a novel method to reverse free-radical induced impairment of cell mechanics is of interest. We thus designed a series of experiments that explored the effects of intracellular superoxide (O2 -) generation on the deformability of RBC and also activation of pivotal molecular pathways known to regulate cell mechanics - i.e., PI3K/Akt kinase and RBC nitric oxide synthase (NOS). In addition, RBC exposed to O2 - were conditioned with specific shear stresses, prior to evaluation of cellular deformability and activation of PI3K/Akt kinase and RBC-NOS. Intracellular generation of O2 - decreased phosphorylation of RBC-NOS at its primary activation site (Ser1177) (p < 0.001), while phosphorylation of Akt kinase at its active residue (Ser473) was also diminished (p < 0.001). Inactivation of these enzymes following O2 - exposure occurred in tandem with decreased RBC deformability. Shear conditioning significantly improved cellular deformability, even in RBC previously exposed to O2 -. The improvement in cellular deformability may have been the result of enhanced molecular signaling, given RBC-NOS phosphorylation in RBC exposed to O2 - was restored following shear conditioning. Impaired RBC deformability induced by intracellular O2 - may be due, in part, to impaired activation of PI3K/Akt, and downstream signaling with RBC-NOS. These findings may shed light on improved circulatory health with targeted promotion of blood flow (e.g., exercise training), and may prove fruitful in future development of blood-contacting devices.

Dataset Information

Genetic deletion of nitric oxide synthase 2 ameliorates Parkinson's disease pathology and neuroinflammation in a transgenic mouse model of synucleinopathy.

Publications

Genetic deletion of nitric oxide synthase 2 ameliorates Parkinson's disease pathology and neuroinflammation in a transgenic mouse model of synucleinopathy.

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