The alteration of RhoA geranylgeranylation and Ras farnesylation breaks the integrity of the blood–testis barrier and results in hypospermatogenesis

Abstract

Non-obstructive azoospermia (NOA) severely affects male infertility, however, the deep mechanisms of this disease are rarely interpreted. In this study, we find that undifferentiated spermatogonial stem cells (SSCs) still exist in the basal compartment of the seminiferous tubules and the blood–testis barrier (BTB) formed by the interaction of neighbor Sertoli cells (SCs) is incomplete in NOA patients with spermatogenic maturation arrest. The adhesions between SCs and germ cells (GCs) are also broken in NOA patients. Meanwhile, the expression level of geranylgeranyl diphosphate synthase ( Ggpps ), a key enzyme in mevalonate metabolic pathway, is lower in NOA patients than that in obstructive azoospermia (OA) patients. After Ggpps deletion specifically in SCs, the mice are infertile and the phenotype of the SC- Ggpps −/− mice is similar to the NOA patients, where the BTB and the SC–GC adhesions are severely destroyed. Although SSCs are still found in the basal compartment of the seminiferous tubules, fewer mature spermatocyte and spermatid are found in SC- Ggpps −/− mice. Further examination suggests that the defect is mediated by the aberrant protein isoprenylation of RhoA and Ras family after Ggpps deletion. The exciting finding is that when the knockout mice are injected with berberine, the abnormal cell adhesions are ameliorated and spermatogenesis is partially restored. Our data suggest that the reconstruction of disrupted BTB is an effective treatment strategy for NOA patients with spermatogenic maturation arrest and hypospermatogenesis.

Bibliometric and visual analysis of blood-testis barrier research

“…Sertoli cell TJs and TJ proteins might be regulated by FSH, testosterone, and paracrine hormones as possible mediators of junction formation and disassembly during the translocation process ( Stanton, 2016 ). These biological breakthroughs have resulted in a slew of new technical advancements in the treatment of male infertility, including the repair of damaged BTB in nonobstructive azoospermia (NOA) patients with spermatogenic maturation arrest and hypospermatogenesis ( Zhu et al, 2019 ) and manipulation of TJ proteins to promote stem cell homing efficiency ( Kanatsu-Shinohara et al, 2018 ).…”

Leukocytospermia in late adolescents: possible clinical interpretations

“…Leukocytospermia is an established marker of inflammation and it has been associated with increased semen levels of interleukin-6 and tumor necrosis factor-α, both inflammatory cytokines, in infertile patients [ 27 ]. Leukocytes are also involved in the pathogenesis of autoimmune inflammation of seminal ducts [ 28 ].…”

Geranylgeranyl diphosphate synthase: Role in human health, disease and potential therapeutic target

“…Based on data from the Human Protein Atlas, GGPS1 expression is highest in the testis which may be related to the essential role of GGDPS in spermatogenesis. 35 , 41 , 42 Expression levels also appear elevated in the eye, skeletal muscle and breast tissue, suggesting that GGDPS may play an important role in these tissues as well. While previous studies have found elevated levels of geranylgeranylated proteins in the human heart, brain, skeletal muscle and testis, variation between geranylgeranylated protein levels and GGPS1 tissue expression may indicate that expression of the synthase does not necessarily correlate with levels of geranylgeranylated proteins.…”