Prolyl Endopeptidase (PREP) is Associated With Male Reproductive Functions and Gamete Physiology in Mice

Abstract

Prolyl endopeptidase (PREP) is a serine protease which has been implicated in many biological processes, such as the maturation and degradation of peptide hormones and neuropeptides, learning and memory, cell proliferation and differentiation, and glucose metabolism. A small number of reports have also suggested PREP participation in both male and female reproduction-associated processes. In the present work, we examined PREP distribution in male germ cells and studied the effects of its knockdown (Prep(gt/gt)) on testis and sperm in adult mice. The protein is expressed and localized in elongating spermatids and luminal spermatozoa of wild type (wt) mice, as well as Sertoli, Leydig, and peritubular cells. PREP is also expressed in the head and midpiece of epididymal spermatozoa, whereas the remaining tail region shows a weaker signal. Furthermore, testis weight, histology of seminiferous tubules, and epididymal sperm parameters were assessed in wt and Prep(gt/gt) mice: wild type testes have larger average tubule and lumen diameter; in addition, lumenal composition of seminiferous tubules is dissimilar between wt and Prep(gt/gt), as the percentage of spermiated tubules is much higher in wt. Finally, total sperm count, sperm motility, and normal morphology are also higher in wt than in Prep(gt/gt). These results show for the first time that the expression of PREP could be necessary for a correct reproductive function, and suggest that the enzyme may play a role in mouse spermatogenesis and sperm physiology.

Prolyl Endopeptidase (PREP) is Involved in the Reproductive Functions and Cytoskeletal Organization in Rat Spermatogenesis and in Mammalian Sperm

“…It is interesting to note, that the endopeptidase is clearly detectable in the tail of isolated epididymal and human SPZ, as well as tubulin, which suggests that the PREP may be involved in mature sperm function. Our data, which match with those found in our previous work by Dotolo et al (2016) in mouse sperm, let us to hypothesize a possible role of the enzyme in mammalian sperm motility: as known, the process is driven by the release and uptake of calcium by intracellular stores (Herrick et al, 2005; Ho and Suarez, 2003), and being PREP a possible regulator of the pathway of inositol 1,4,5 which results in the modulation of cytosolic calcium level (Szeltner and Polgár, 2008) we suggest that PREP, through its involvement in calcium signalling, might be an actor in the regulation of sperm movement and progression. As known, the motility is generated by the internal cytoskeletal structure called axoneme, a highly organized microtubule-based structure constructed from approximately 250 proteins that has been well conserved through evolution (Inaba, 2003).…”

“…Later analyses on human showed that PREP localizes in the seminiferous tubules and Leydig cells and proposed that it may participate in regulating the levels of seminal TRH analogues, mediating death associated with necrozoospermia (Valdivia et al, 2004; Myöhänen et al, 2012). Finally, in our previous work (Dotolo et al, 2016) we studied the effects of PREP knockdown on testis and sperm in adult mice, showing that the enzyme is indeed needed for a correct reproductive function and that its absence leads to marked alterations of the gonads and, ultimately, gametes. All these reports suggest that PREP might have an active role in male reproductive function.…”

“…Since cytoskeletal remodeling is a critical feature which allows the cell to modulate its shape and architecture, the study of its actors during gametogenesis and reproduction is of great interest, as the germinal compartment and the germ cells undergo a complex series of transformations throughout the process (Venditti and Minucci, 2017), led by heavy cytoskeletal elements organization (Lie et al, 2010). So far, only a few reports have already suggested PREP participation in both male and female reproduction-associated processes (Kimura et al, 1998; Kimura et al, 2002; Dotolo et al, 2016). Thus, in this work, we assessed the possible association of PREP with the morphogenesis of rat testis, by studying and comparing its expression and localization with tubulin, during the first wave of spermatogenesis and in the adult tissue.…”

Prolyl oligopeptidase regulates progesterone secretion via the ERK signaling pathway in murine luteal cells

“…POP can induce apoptosis by binding to glyceraldehyde-3-phosphate dehydrogenase (GAPDH), a potential pathogenic factor in Alzheimer's disease (Mantle, Falkous, Ishiura, Blanchard, & Perry, 1996;Matsuda et al, 2013). In the testis, POP affects sperm movement and progression by regulating calcium signaling (Dotolo, Kim, Pariante, Minucci, & Diano, 2016).…”

“…The corpus luteum, which differentiates from the dominant ovarian follicle after ovulation, is a temporary and dynamic endocrine gland (Bachelot & Binart, 2005;van den Driesche, Smith, Myers, & Duncan, 2008). It is mainly composed of steroidogenic cells, including granulosa and theca-luteal cells, and endothelial cells.…”