Proprotein convertase subtilisin/kexin type 4 in mammalian fertility: a review

Gyamera-Acheampong, Charles; Mbikay, Majambu

doi:10.1093/humupd/dmn060

Cited by 39 publications

(29 citation statements)

References 119 publications

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“…Further, PC2 together with PC1 generates insulin through endoproteolytic processing of preproinsulin (Bailyes et al, 1991; Seidah and Prat, 2012; Steiner et al, 1996). IGF-2 has been found to be processed by PC4 in other tissues (Qiu et al, 2005; Tani et al, 2008); in fact, this enzyme subtype is exclusively expressed in testicular germ cells in males and in the placenta and ovary in females (Gyamera-Acheampong and Mbikay, 2009; Seidah and Prat, 2012), and therefore it is unlikely that PC4 is responsible for IGF-2 processing in the brain. We suggest that in the brain PC2 and/or PC2 together with PC1 process precursor forms of IGF-2 into mature IGF-2, and identifying approaches that reduce PC2 deficits may also be an interesting and novel avenue for developing therapies against cognitive impairments.…”

Section: Discussionmentioning

confidence: 99%

Insulin-like growth factor 2 rescues aging-related memory loss in rats

Steinmetz

Johnson

Iannitelli

et al. 2016

Neurobiology of Aging

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Aging is accompanied by declines in memory performance, and particularly affects memories that rely on hippocampal-cortical systems, such as episodic and explicit. With aged populations significantly increasing, the need for preventing or rescuing memory deficits is pressing. However, effective treatments are lacking. Here we show that the level of the mature form of insulin-like growth factor 2 (IGF-2), a peptide regulated in the hippocampus by learning, required for memory consolidation and a promoter of memory enhancement in young adult rodents, is significantly reduced in hippocampal synapses of aged rats. By contrast the hippocampal level of the immature form proIGF-2 is increased, suggesting an aging-related deficit in IGF-2 processing. In agreement, aged compared to young adult rats are deficient in the activity of proprotein convertase 2, an enzyme that likely mediates IGF-2 post-translational processing. Hippocampal administration of the recombinant, mature form of IGF-2 rescues hippocampal-dependent memory deficits as well as working memory impairment in aged rats. Thus, IGF-2 may represent a novel therapeutic avenue for preventing or reversing aging-related cognitive impairments.

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Section: Discussionmentioning

confidence: 99%

Insulin-like growth factor 2 rescues aging-related memory loss in rats

Steinmetz

Johnson

Iannitelli

et al. 2016

Neurobiology of Aging

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“…Our pharmacological experiments showed that PMSF and furin inhibitors (Dec-RVKR-CMK and hexa-Darginine) inhibited the activation of PLB during sterol removal, whereas benzamidine, trypsin inhibitor, and leupeptin did not. Furin belongs to the proprotein convertase subtilisin/kexin type (PCSK) family consisting of nine serine endoproteases (55). Studies with transcriptome analysis and immunolocalization identified that PCSK3 (furin), PCSK4, and PCSK7 (56 -58) are expressed in the testis.…”

Section: Discussionmentioning

confidence: 99%

Phospholipase B Is Activated in Response to Sterol Removal and Stimulates Acrosome Exocytosis in Murine Sperm

Asano

Nelson-Harrington

Travis

2013

Journal of Biological Chemistry

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Background: How sperm sterol removal enables acrosome exocytosis (AE) is unclear; phospholipase B (PLB) is enriched in sperm membrane rafts. Results: Sterol removal leads to proteolytic activation of PLB, stimulating the initiation of changes leading to AE. Conclusion: PLB activation plays an important role in fertilization. Significance: We identify a mechanism for how sterol removal enables AE, consistent with new, zona pellucida-independent models for membrane fusion.

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“…Pc4 2/2 mice do not show any altered spermatogenesis, but spermatozoa exhibit accelerated capacitation, precocious acrosome reaction, and reduced spermatozoa-egg binding ability that is only half that of wild-type mice. Eggs fertilized by these sperm fail to grow to the blastocyst stage (Gyamera-Acheampong and Mbikay, 2009;Gyamera-Acheampong et al, 2006;Mbikay et al, 1997).…”

Section: Microscopy Research and Techniquementioning

confidence: 99%

Surfing the wave, cycle, life history, and genes/proteins expressed by testicular germ cells. Part 3: Developmental changes in spermatid flagellum and cytoplasmic droplet and interaction of sperm with the zona pellucida and egg plasma membrane

Hermo¹,

Pelletier²,

Cyr³

et al. 2009

Microscopy Res & Technique

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Spermiogenesis constitutes the steps involved in the metamorphosis of spermatids into spermatozoa. It involves modification of several organelles in addition to the formation of several structures including the flagellum and cytoplasmic droplet. The flagellum is composed of a neck region and middle, principal, and end pieces. The axoneme composed of nine outer microtubular doublets circularly arranged to form a cylinder around a central pair of microtubules is present throughout the flagellum. The middle and principal pieces each contain specific components such as the mitochondrial sheath and fibrous sheath, respectively, while outer dense fibers are common to both. A plethora of proteins are constituents of each of these structures, with each playing key roles in functions related to the fertility of spermatozoa. At the end of spermiogenesis, a portion of spermatid cytoplasm remains associated with the released spermatozoa, referred to as the cytoplasmic droplet. The latter has as its main feature Golgi saccules, which appear to modify the plasma membrane of spermatozoa as they move down the epididymal duct and hence may be partly involved in male gamete maturation. The end product of spermatogenesis is highly streamlined and motile spermatozoa having a condensed nucleus equipped with an acrosome. Spermatozoa move through the female reproductive tract and eventually penetrate the zona pellucida and bind to the egg plasma membrane. Many proteins have been implicated in the process of fertilization as well as a plethora of proteins involved in the development of spermatids and sperm, and these are high lighted in this review.

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Proprotein convertase subtilisin/kexin type 4 in mammalian fertility: a review

Abstract: PCSK4 appears to be a crucial enzyme for reproduction. Alterations of PCSK4 expression or activity could be the underlying cause of some unexplained cases of human infertility. Conversely, inactivation of this protease represents a potential strategy for non-hormonal contraception.

Cited by 39 publications

References 119 publications

Insulin-like growth factor 2 rescues aging-related memory loss in rats

Insulin-like growth factor 2 rescues aging-related memory loss in rats

Phospholipase B Is Activated in Response to Sterol Removal and Stimulates Acrosome Exocytosis in Murine Sperm

Surfing the wave, cycle, life history, and genes/proteins expressed by testicular germ cells. Part 3: Developmental changes in spermatid flagellum and cytoplasmic droplet and interaction of sperm with the zona pellucida and egg plasma membrane

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