WIKIMEDIA, GEORGE SHUKLINThough many diseases arise because the protein product of a gene does not function correctly, others occur because misfolded proteins get stuck in the endoplasmic reticulum or are degraded before arriving at the site where they should act in the cell. Scientists have explored the use of small molecules called pharmacological chaperones, which bind misfolded proteins and stabilize them or act as templates that encourage the molecules to fold correctly, in order to treat lysosomal storage diseases, familial amyloid polyneuropathy, phenylketonuria, and other disorders of protein folding. Now, researchers led by P. Michael Conn of Texas Tech University have shown that a mouse model that does not respond to gonadotrophin-releasing hormone (GnRH) due to a mutation that causes misfolding of the GnRH receptor (GnRHR) can be treated with a pharmacological chaperone. Their work was published today in Proceedings of the National Academy of Sciences.
“I think chemical chaperones are a terrific idea,” said Dagmar Ringe, a professor of biochemistry and chemistry at Brandeis University in Waltham, Massachusetts, who was not involved in the work. “It’s a great way of approaching a problem that hasn’t been really appreciated in the sense that we’re talking about unstable or . . . misfolded proteins. There are so many cases where this type of intervention would actually be really useful.”
Conn’s group generated a mouse model with a mutation that can result in the human disease hypogonadotropic hypogonadism (HH), in which a misfolded GnRH receptor causes loss of testis or ovary function. The male mice with this mutation had small testes, produced few mature sperm, and had abnormal levels of testosterone. The female ...
