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

Whelly, Sandra; Serobian, Gaiane; Borchardt, Clinton; Powell, Jonathan; Johnson, Seethal; Håkansson, Katarina LU ; Lindström, Veronica LU ; Abrahamson, Magnus LU ; Grubb, Anders LU and Cornwall, Gail A. (2014) In Journal of Biological Chemistry 289(11). p.7718-7729
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... (More)
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. (Less)
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author
organization
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type
Contribution to journal
publication status
published
subject
keywords
Amyloid, Animal models, Epididymis, Neurodegenerative Diseases, Protein, Aggregation, Reproduction, Spermatozoa, Cystatin C, Hereditary Cystatin, c Amyloid Angiopathy, Male Fertility
in
Journal of Biological Chemistry
volume
289
issue
11
pages
7718 - 7729
publisher
ASBMB
external identifiers
  • wos:000332761500039
  • scopus:84896277037
ISSN
1083-351X
DOI
10.1074/jbc.M113.515759
language
English
LU publication?
yes
id
48354645-9006-48a8-8afc-e82d53d8259b (old id 4470212)
date added to LUP
2014-07-01 07:39:53
date last changed
2017-07-23 03:27:02
@article{48354645-9006-48a8-8afc-e82d53d8259b,
  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.},
  author       = {Whelly, Sandra and Serobian, Gaiane and Borchardt, Clinton and Powell, Jonathan and Johnson, Seethal and Håkansson, Katarina and Lindström, Veronica and Abrahamson, Magnus and Grubb, Anders and Cornwall, Gail A.},
  issn         = {1083-351X},
  keyword      = {Amyloid,Animal models,Epididymis,Neurodegenerative Diseases,Protein,Aggregation,Reproduction,Spermatozoa,Cystatin C,Hereditary Cystatin,c Amyloid Angiopathy,Male Fertility},
  language     = {eng},
  number       = {11},
  pages        = {7718--7729},
  publisher    = {ASBMB},
  series       = {Journal of Biological Chemistry},
  title        = {Fertility Defects in Mice Expressing the L68Q Variant of Human Cystatin C A ROLE FOR AMYLOID IN MALE INFERTILITY},
  url          = {http://dx.doi.org/10.1074/jbc.M113.515759},
  volume       = {289},
  year         = {2014},
}