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Regulation of brain aging by neutral sphingomyelinase 2

ABSTRACT: Regulation of brain aging by neutral sphingomyelinase 2

PROVIDER: PRJNA742012 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR14930804_1.fastq.gz	Fastqsanger.gz
	SRR14930804_2.fastq.gz	Fastqsanger.gz
	SRR14930805_1.fastq.gz	Fastqsanger.gz
	SRR14930805_2.fastq.gz	Fastqsanger.gz
	SRR14930806_1.fastq.gz	Fastqsanger.gz

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Regulation of brain aging by neutral sphingomyelinase 2

Project description:Purpose: The goals of this study are to compare next generation sequencing-derived brain cortex transcriptome profiling (RNA-seq) to study the role of neutral sphingomyelinase 2 (smpd3) in brain aging. Methods: Brain cortex mRNA profiles of 10 month old (fro/+) and smpd3 total knockout (fro/fro) mice were generated by deep sequencing, in duplicate, using Illumina NovaSeq 6000. (https://en.novogene.com) Results:A total of 1462 transcripts differed between genotypes, with 891 transcripts increased and 571 transcripts decreased. Conclusions: Transcriptome differences link decreased oxidative stress and astrocyte activation in brain cortex to nSMase2 deficiency, while synaptic signaling transcripts increased in ways consistent with increased cognitive function previously demonstrated in nSMase2-deficient mice.

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Loss of ER and nuclear envelope-associated neutral sphingomyelinase SMPD4 causes a severe neurodevelopmental disorder with microcephaly and congenital arthrogryposis

Project description:Several neurodevelopmental processes including neuronal survival, migration and differentiation are controlled by sphingolipid metabolism. Sphingomyelin is an abundant component of cell membranes. Sphingomyelinases generate ceramide from sphingomyelin as a second messenger in intracellular signaling pathways involved in cell proliferation, differentiation, or apoptosis. While the role of acid sphingomyelinase is well established, the role of neutral sphingomyelinases in human neurodevelopment has remained elusive. Twenty-five children from ten unrelated families presented with microcephaly with simplified gyral pattern, cerebellar hypoplasia, severe developmental encephalopathy, congenital arthrogryposis, diabetes mellitus and early fetal/-postnatal demise. All probands tested have biallelic loss of function variants in SMPD4, coding for neutral sphingomyelinase-3 (nSMase-3 / SMPD4). Fibroblasts from affected individuals showed morphologic endoplasmic reticulum (ER) cisternae abnormalities and increased autophagy, consistent with a previously suggested function of SMPD4 in the ER. Overexpression of human Myc-tagged SMPD4 in HEK293T cells showed localization to both the outer nuclear envelope and the ER. Previous studies localized SMPD4 to the outer nuclear membrane. Mass spectrometry of SMPD4-associated proteins detected peptides belonging to nuclear pore complex proteins. After downregulation of SMPD4 by siRNA, delayed cell cycle progression was observed and primary fibrobalsts from affected individuals were more prone to apoptosis than controls. These data are consistent with former studies in HeLa cells showing mitotic abnormalities after siSMPD4 treatment. This study provides a link between sphingolipid membrane homeostasis, cell fate and mitotic decisions indicating novel pathway in the pathogenesis of microcephaly.

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