Prm2 deficiency triggers a Reactive Oxygen Species (ROS)-mediated destruction cascade during epididymal sperm maturation in mice
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ABSTRACT:
PROVIDER: PRJNA628706 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR11616330.fastq.gz | Fastqsanger.gz | |||
| SRR11616331.fastq.gz | Fastqsanger.gz | |||
| SRR11616332.fastq.gz | Fastqsanger.gz | |||
| SRR11616333.fastq.gz | Fastqsanger.gz | |||
| SRR11616334.fastq.gz | Fastqsanger.gz |
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Project description:Protamines are the safeguards of the paternal sperm genome. They replace most of the histones during spermiogenesis, resulting in DNA hypercondensation, thereby protecting its genome from environmental noxa. Impaired protamination has been linked to male infertility in mice and humans in many studies. Apart from impaired DNA integrity, protamine-deficient human and murine sperm show multiple secondary effects, including decreased motility and aberrant head morphology. In this study, we use a Prm2-deficient mouse model in combination with label-free quantitative proteomics to decipher the underlying molecular processes of these effects. We show that loss of the sperm`s antioxidant capacity, indicated by downregulation of key proteins like SOD1 and PRDX5, ultimately initiates an oxidative stress-mediated destruction cascade during epididymal sperm maturation. This is confirmed by an increased level of 8-OHdG in epididymal sperm, a biomarker for oxidative stress-mediated DNA damage. Prm2-deficient testicular sperm are not affected and initiate the proper development of blastocyst stage preimplantation embryos in vitro upon intracytoplasmic sperm injection (ICSI) into oocytes. Our results provide new insight into the role of Prm2 and its downstream molecular effects on sperm function and present an important contribution to the investigation of new treatment regimens for infertile men with impaired protamination.
2020-07-29 | GSE149454 | GEO
Project description:MTD project_description Protamines are testis-specific proteins, which replace the majority of histones during spermiogenesis. This results in a hypercondensation of the sperm DNA, finally causing a conformational change from a nucleosomal chromatin structure into a mainly toroid like structure. This is assumed to protect the paternal genome and to contribute to the formation of a hydrodynamic sperm head shape. In mice and humans, two protamines, Protamine 1 (Prm1) and Protamine 2 (Prm2), are expressed. Impaired sperm protamination has been repeatedly correlated with male subfertility in mice and humans. Apart from defects in DNA condensation and impaired DNA integrity, protamine-deficient human and murine sperm show multiple secondary defects, which cannot be explained by the chromosomal function of protamines. These include impaired sperm motility, decreased viability as well as acrsosomal malformations. In this study, we utilized a Prm2-deficient mouse model to investigate the underlying molecular mechanisms of these defects. Since trancription is silenced upon incorporation of protamines, we used LC-MS in combination with label-free quantification to compare the sperm proteome of Prm2-deficient (Prm2-/-) males with the proteome of wildtype (Prm2+/+) and Prm2 heterozygous (Prm2+/-) males. We show that Prm2 deficient mice display a strongly altered proteomic profile compared to controls. Of note, a significant downregulation of proteins SOD1 and PRDX5, which have a well-known function for the detoxification of reactive oxygen species was observed. Thus, together with a series of additional experiments, we could for the first time show that Prm2-deficiency triggers a reactive oxygen species (ROS) mediated sperm destruction cascade during epididymal sperm maturation, finally causing described secondary sperm defects.
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Project description:Protamines are the safeguards of the paternal sperm genome. They replace most of the histones during spermiogenesis, resulting in DNA hypercondensation, thereby protecting its genome from environmental noxa. Impaired protamination has been linked to male infertility in mice and humans in many studies. Apart from impaired DNA integrity, protamine-deficient human and murine sperm show multiple secondary effects, including decreased motility and aberrant head morphology. In this study, we use a Protamine-2 (Prm2)-deficient mouse model in combination with label-free quantitative proteomics to decipher the underlying molecular processes of these effects. We show that loss of the sperm's antioxidant capacity, indicated by downregulation of key proteins like Superoxide dismutase type 1 (SOD1) and Peroxiredoxin 5 (PRDX5), ultimately initiates an oxidative stress-mediated destruction cascade during epididymal sperm maturation. This is confirmed by an increased level of 8-OHdG in epididymal sperm, a biomarker for oxidative stress-mediated DNA damage. Prm2-deficient testicular sperm are not affected and initiate the proper development of blastocyst stage preimplantation embryos in vitro upon intracytoplasmic sperm injection (ICSI) into oocytes. Our results provide new insight into the role of Prm2 and its downstream molecular effects on sperm function and present an important contribution to the investigation of new treatment regimens for infertile men with impaired protamination.
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Project description:Nutrient deprivation triggers the release of signal-sequence-lacking antioxidant superoxide dismutase 1 (SOD1). We now report that secreted SOD1 is functionally active and accompanied by export of other antioxidant enzymes such as thioredoxins, (Trx1 and Trx2) and peroxiredoxin Ahp1. Our data reveal that starvation increases mitochondrial activity, which generates higher, but non-toxic, levels of reactive oxygen species (ROS). Inhibiting mitochondrial activity or ROS prevents antioxidants secretion. We suggest that in response to ROS production that can permeate the plasma membrane, the cells respond by secreting antioxidants to prevent ROS-mediated damage in the extracellular space. These findings provide an understanding of why cells secrete signal sequence lacking antioxidant enzymes in response to starvation.
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Project description:Signal-sequence-lacking superoxide dismutase 1 (SOD1) is secreted upon nutrient starvation, but the physiological relevance of this secretion is unclear. We now report that secreted SOD1 is functionally active. In addition, a secretome analysis has revealed number of other secreted cytoplasmic antioxidant enzymes, including both thioredoxins, (Trx1 and Trx2), and the peroxiredoxin Ahp1. Our data reveal that starvation triggers increased mitochondrial activity, leading to increased production of reactive oxygen species (ROS). Inhibiting mitochondrial activity or ROS, inhibited secretion of the antioxidants. We suggest elevated ROS that evade cytoplasmic antioxidants, can permeate across the plasma membrane to the extracellular space. Cells secrete antioxidants to prevent ROS-mediated damage to the extracellular space. These findings thus provide an understanding of why cells secrete signal sequence lacking proteins like SOD1 and the larger family of antioxidants.
2019-05-14 | PXD010849 | Pride
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2016-04-03 | E-GEOD-79855 | biostudies-arrayexpress
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