Fertility Defects in Mice Expressing the L68Q Variant of Human Cystatin C A ROLE FOR AMYLOID IN MALE INFERTILITY

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Abstract

Background: The L68Q variant of cystatin C is highly amyloidogenic forming aggregates in individuals with HCCAA. Results: Spermatozoa from mice expressing human L68Q cystatin C exhibit fertility defects and increased levels of amyloid. Conclusion: L68Q epididymal fluid containing cystatin C amyloid is harmful for sperm function. Significance: Amyloid in the reproductive tract may contribute to male factor infertility. Hereditary cystatin C amyloid angiopathy is an autosomal dominant disorder in which a variant form of cystatin C (L68Q) readily forms amyloid deposits in cerebral arteries in affected individuals resulting in early death. L68Q protein deposits in human cystatin C amyloid angiopathy patients have also been found in tissues outside of the brain including the testis, suggesting possible effects on fertility. Heterozygous transgenic mice (L68Q) that express the human L68Q variant of cystatin C under the control of the mouse cystatin C promoter were unable to generate offspring, suggesting the presence of L68Q cystatin C amyloid affected sperm function. In vitro studies showed that epididymal spermatozoa from L68Q mice were unable to fertilize oocytes and exhibited poor sperm motility. Furthermore, spermatozoa from L68Q mice exhibited reduced cell viability compared with wild type (WT) spermatozoa and often were detected in large agglutinated clumps. Examination of the epididymal fluid and spermatozoa from L68Q mice showed increased levels and distinct forms of cystatin C amyloid that were not present in WT mice. The addition of epididymal fluid from L68Q mice to WT spermatozoa resulted in a recapitulation of the L68Q phenotype in that WT spermatozoa showed reduced cell viability and motility compared with WT spermatozoa incubated in epididymal fluid from WT mice. L68Q epididymal fluid that was depleted of cystatin C amyloids, however, did not impair the motility of WT spermatozoa. Taken together these studies suggest that amyloids in the epididymal fluid can be cytotoxic to the maturing spermatozoa resulting in male infertility.

Detaljer

Författare
Enheter & grupper
Forskningsområden

Ämnesklassifikation (UKÄ) – OBLIGATORISK

  • Farmakologi och toxikologi
  • Läkemedelskemi

Nyckelord

Originalspråkengelska
Sidor (från-till)7718-7729
TidskriftJournal of Biological Chemistry
Volym289
Utgåva nummer11
StatusPublished - 2014
PublikationskategoriForskning
Peer review utfördJa