التفاصيل البيبلوغرافية
| العنوان: |
Restoration of testis function in hypogonadotropic hypogonadal mice harboring a misfolded GnRHR mutant by pharmacoperone drug therapy. |
| المؤلفون: |
Janovick, Jo Ann, David Stewart, M., Jacob, Darla, Martin, L. D., Deng, Jian Min, Allison Stewart, C., wang, Ying, Cornea, Anda, Chavali, Lakshmi, Lopez, Suhujey, Mitalipov, Shoukhrat, Kang, Eunju, Lee, Hyo-Sang, Manna, Pulak R., Stocco, Douglas M., Behringer, Richard R., Michael Conn, P. |
| المصدر: |
Proceedings of the National Academy of Sciences of the United States of America; 12/24/2013, Vol. 110 Issue 52, p21030-21035, 6p |
| مصطلحات موضوعية: |
PROTEINS, GONADOTROPIN, ENDOCRINE glands, HORMONES, ENDOCRINOLOGY |
| مستخلص: |
Mutations in receptors, ion channels, and enzymes are frequently recognized by the cellular quality control system as misfolded and retained in the endoplasmic reticulum (ER) or otherwise misrouted. Retention results in loss of function at the normal site of biological activity and disease. Pharmacoperones are target-specific small molecules that diffuse into cells and serve as folding templates that enable mutant proteins to pass the criteria of the quality control system and route to their physiologic site of action. Pharmacoperones of the gonadotropin releasing hormone receptor (GnRHR) have efficacy in cell culture systems, and their cellular and biochemical mechanisms of action are known. Here, we show the efficacy of a pharmacoperone drug in a small animal model, a knockin mouse, expressing a mutant GnRHR. This recessive muta- tion (GnRHR E90K) causes hypogonadotropic hypogonadism (failed puberty associated with low or apulsatile luteinizing hormone) in both humans and in the mouse model described. We find that pulsatile pharmacoperone therapy restores E90K from ER retention to the plasma membrane, concurrently with responsiveness to the endogenous natural ligand, gonadotropin releasing hormone, and an agonist that is specific for the mutant. Spermatogenesis, proteins associated with steroid transport and steroidogenesis, and androgen levels were restored in mutant male mice following pharmacoperone therapy. These results show the efficacy of pharmacoperone therapy in vivo by using physiological, molecular, genetic, endocrine and biochemical markers and optimization of pulsatile administration. We expect that this newly appreciated approach of protein rescue will benefit other disorders sharing pathologies based on misrouting of misfolded protein mutants. [ABSTRACT FROM AUTHOR] |
|
Copyright of Proceedings of the National Academy of Sciences of the United States of America is the property of National Academy of Sciences and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.) |
| قاعدة البيانات: |
Complementary Index |
Full Text Finder