Abstract
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.
Highlights
The L68Q variant of cystatin C is highly amyloidogenic forming aggregates in individuals with hereditary form of cystatin C amyloid angiopathy (HCCAA)
As shown below, both mouse and human cystatin C proteins were expressed in the heterozygous L68Q mouse, whereas only mouse cystatin C was present in the wild type (WT) mice
L68Q cystatin C deposits are present in organs outside of the brain including the testis, less is known regarding the pathophysiology of these inclusions since the primary cause of death in affected individuals is due to cerebral hemorrhage [36, 37]
Summary
Sandra Whelly‡, Gaiane Serobian‡, Clinton Borchardt‡, Jonathan Powell‡, Seethal Johnson‡, Katarina Hakansson§, Veronica Lindstrom§, Magnus Abrahamson§, Anders Grubb§, and Gail A. Cornwall‡1 From the ‡Department of Cell Biology and Biochemistry, Texas Tech University Health Sciences Center, Lubbock, Texas 79430 and §Department of Clinical Chemistry and Pharmacology, University of Lund, S-22185 Lund, Sweden
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