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T Cell Infiltration in Central Nervous System and Their Association with Brain Calcification in Slc20a2-deficient Mice

ABSTRACT: T Cell Infiltration in Central Nervous System and Their Association with Brain Calcification in Slc20a2-deficient Mice

PROVIDER: PRJNA903169 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR22334887_1.fastq.gz	Fastqsanger.gz
	SRR22334887_2.fastq.gz	Fastqsanger.gz
	SRR22334888_1.fastq.gz	Fastqsanger.gz
	SRR22334888_2.fastq.gz	Fastqsanger.gz
	SRR22334889_1.fastq.gz	Fastqsanger.gz

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Project description:Primary familial brain calcification (PFBC) is a rare neurodegenerative and neuropsychiatric disorder characterized by bilateral and symmetric brain calcification along the microvessels or inside neuronal cells in the basal ganglia, thalamus, and cerebellum. Neurological symptoms typically include movement disorders, cognitive impairment, and neuropsychiatric signs. Slc20a2 homozygous (HO) knockout mice can simulate the phenotype of brain calcification observed in humans. However, the cellular and molecular mechanisms associated with brain calcification, particularly at an extremely early stage (before calcification emerges), remain largely unknown. Herein, we quantified central nervous system (CNS)-infiltrating immune cells in different age groups and found that CD45+CD3+ T cells were significantly increased in the brain parenchyma even in the pre-calcification stage of 1-month-old Slc20a2-HO mice. Further immunophenotyping demonstrated that CD3+CD4-CD8- and CD3+CD4+ T cells were the two main subtypes increased in the brain. The accumulation of total T cells appears to be associated with the severity of brain calcification. Paracellular and transcellular permeability of the blood-brain barrier increased in endothelial cells of brain microvessels in Slc20a2-HO mice. The expression of endothelial cell adhesion molecules was increased, while that of tight and adherens junction proteins was decreased, reflecting the molecular basis of T cell recruitment to endothelial cells and paracellular migration into the brain. IgG and albumin assays revealed an increased leakage of endothelial cells and the process of T cell transcellular migration was captured by immunoelectron microscopy, suggesting the enhancement of transcytosis or endocytosis in brain endothelial cells of Slc20a2-HO mice. The sphingosine 1-phosphate receptor modulator, FTY720, could significantly inhibit brain calcification, probably by reducing the CNS infiltration of T cells, subsequently modulating neuroinflammation, and enhancing the phagocytosis of CNS resident immune cells. This study demonstrated that CNS-infiltrating T cells were associated with the progression of brain calcification and suggested that the impairment of blood-brain barrier permeability, which was closely related to T cell invasion into the CNS, could be explained by an increase in the paracellular and transcellular pathways of brain endothelial cells in Slc20a2-HO mice. Moreover, FTY720 was a potential drug that could be used to treat patients with PFBC in the future

Project description:Shelled pteropods play key roles in the global carbon cycle and foodwebs of various ecosystems. Their thin external shell is extremely sensitive to changes in pH and shell dissolution has already been observed in areas where aragonite saturation state is ~ 1. A decline in pteropod abundance has the potential to disrupt trophic networks and directly impact commercial fisheries. Therefore it is crucial to understand how pteropods will be affected by global environmental change, particularly ocean acidification. In the present study, physiological and molecular approaches were used to investigate the response of the Mediterranean pteropod, Heliconoides inflatus, to pH values projected for 2100 under a moderate emissions trajectory (RCP6.0). Pteropods were subjected to pHT 7.9 for 3d and gene expression levels, calcification and respiration rates measured relative to pHT 8.1 controls. Gross calcification decreased markedly under low pH conditions, while genes potentially involved in calcification were up-regulated, reflecting the inability of pteropods to maintain calcification rates. Gene expression data imply that under low pH conditions both metabolic processes and protein synthesis may be compromised, while genes involved in acid-base regulation were up-regulated. A large number of genes related to nervous system structure and function were also up-regulated in the low pH treatment, including a GABAA receptor subunit. This is particularly interesting because GABAA receptor disturbances, leading to altered behaviour, have been documented in several other marine animals after exposure to elevated CO2. The up-regulation of many genes involved in nervous system function suggests that, in addition to its impacts on other aspects of biology, exposure to low pH could have major effects on pteropod behavior. This study not only illustrates the utility of combining physiological and molecular approaches, but also highlights the desirability of including behavioural analyses in studies aimed at understanding the impacts of low pH on marine animals.

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T Cell Infiltration in Central Nervous System and Their Association with Brain Calcification in Slc20a2-deficient Mice

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