Fertility Defects in Mice Expressing the L68Q Variant of Human Cystatin C

Whelly, Sandra; Serobian, Gaiane; Borchardt, Clinton; Powell, Jonathan R.; Johnson, Seethal; Håkansson, Katarina; Lindström, Veronica; Abrahamson, Magnus; Grubb, Anders

doi:10.1074/jbc.m113.515759

Cited by 19 publications

(24 citation statements)

References 52 publications

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“…These deposits are mainly composed of the L68Q hCC variant, which shows a naturally high potential for dimerization and self‐association, and is highly amyloidogenic . Further experiments indicated that the presence of L68Q hCC in epididymal fluid may damage mice spermatozoa and reduce male fertility . Therefore, while the structure of monomeric hCC serves as a first goal toward understanding the protein's interactions with proteases, higher order oligomer structures appear to play a role in some diseases associated with hCC.…”

Section: Understanding Hcc Monomer Structurementioning

confidence: 99%

Human cystatin C monomer, dimer, oligomer, and amyloid structures are related to health and disease

et al. 2016

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Human cystatin C (hCC) is a small protein belonging to the cystatin family of papain-like cysteine proteinase inhibitors. We review the recent literature concerning structural aspects of hCC related to disease. We focus on the mechanisms of hCC dimerization, oligomerization, and amyloid formation. Amyloid formation is associated with a number of neurodegenerative diseases that affect the independence and quality of life of aging populations. hCC is one of the second-wave proteins that have been found to undergo amyloidosis associated with disease. For hCC, this includes cerebral amyloid angiopathy, as well as a disorder resulting in reduced male fertility.

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Section: Understanding Hcc Monomer Structurementioning

confidence: 99%

Human cystatin C monomer, dimer, oligomer, and amyloid structures are related to health and disease

et al. 2016

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“…As the most abundant protein, Cst C was found in tissues outside of the brain including the testis, and so was the L68Q variant 70 . A recent study reports that heterozygous transgenic mice that express this pathogenic variant were unable to generate offspring, indicating the L68Q Cst C amyloid affects sperm function 71 . Further analysis of the L68Q mice demonstrated that their epididymal spermatozoa were unable to fertilize oocytes and exhibited poor sperm motility in the presence of Cst C amyloid that were not found in the wild‐type mice.…”

Section: Pathophysiological Roles Of Cst Cmentioning

confidence: 99%

Cystatin C is a disease‐associated protein subject to multiple regulation

Ding

et al. 2015

Immunol Cell Biol

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A protease inhibitor, cystatin C (Cst C), is a secreted cysteine protease inhibitor abundantly expressed in body fluids. Clinically, it is mostly used to measure glomerular filtration rate as a marker for kidney function due to its relatively small molecular weight and easy detection. However, recent findings suggest that Cst C is regulated at both transcriptional and post-translational levels, and Cst C production from haematopoietic cell lineages contributes significantly to the systematic pools of Cst C. Furthermore, Cst C is directly linked to many pathologic processes through various mechanisms. Thus fluctuation of Cst C levels might have serious clinical implications rather than a mere reflection of kidney functions. Here, we summarize the pathophysiological roles of Cst C dependent and independent on its inhibition of proteases, outline its change of expression by various stimuli, and elucidate the regulatory mechanisms to control this disease-related protease inhibitor. Finally, we discuss the clinical implications of these findings for translational gains.

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“…It is primarily divided into three regions, namely caput, corpus, and cauda. are localized on the sperm surface and aid in sperm maturation and function (Li et al, 2001;Hall et al, 2002;Narmadha et al, 2011;Srakaew et al, 2014;Whelly et al, 2014;Narmadha & Yenugu, 2016). During the transit in this organ system, spermatozoa acquire motility and fertilizing ability and this is thought to be achieved because of their interaction with a wide variety of proteins secreted by epithelial cells.…”

Section: Introductionmentioning

confidence: 99%

shRNA mediated ablation of prostate and testis expressed (Pate) messenger RNA results in impaired sperm function and fertility

Rajesh

Yenugu

2017

Andrology

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Spermatogenesis and sperm maturation are complex processes mediated by a variety of proteins present in the testicular and epididymal mileu. In the recent years, functional characterization of these proteins is being studied by genetic manipulations that involve targeted over expression or knock down of specific genes. In this study, we adopted FuGENE 6-based in vivo transfection of rat cauda epididymis with pGFP-V-RS plasmid that encodes shRNA to knock down Pate mRNA levels to implicate a possible role for this gene in sperm function. The mRNA levels of Pate gene were significantly decreased in HEK cells as well as in cauda of rats upon transfection with pGFP-V-RS plasmid that encodes shRNA targeting Pate gene. Spermatozoa obtained from the transfected cauda displayed impairment in capacitation and acrosome reaction. Furthermore, rats subjected to in vivo transfection to knock down Pate mRNA levels had compromised fertility. Results of our study indicate a role for Pate gene in sperm function and can be exploited as a potential male contraceptive target.

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Fertility Defects in Mice Expressing the L68Q Variant of Human Cystatin C

Cited by 19 publications

References 52 publications

Human cystatin C monomer, dimer, oligomer, and amyloid structures are related to health and disease

Human cystatin C monomer, dimer, oligomer, and amyloid structures are related to health and disease

Cystatin C is a disease‐associated protein subject to multiple regulation

shRNA mediated ablation of prostate and testis expressed (Pate) messenger RNA results in impaired sperm function and fertility

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