Inborn errors of metabolism comprise a large class of genetic diseases involving disorders of cellular metabolism. Homocysteine is an intermediary metabolite derived from methionine. It can either be recycled back to methionine, or shunted down the transsulfuration pathway by the action of cystathionine beta-synthase (CBS). Individuals with mutations in CBS have clinical CBS deficiency, characterized by extreme elevations in plasma total homocysteine (tHcy) and phenotypes including increased incidence of thrombosis, osteoporosis, dislocated lenses, and mental retardation. Current treatment strategies involve dietary restriction and vitamin therapy, but these are only partially effective and do not work in all patients. Over 85% of the described mutations in CBS deficient patients are missense mutations in which a single incorrect amino acid is substituted into the CBS polypeptide. These mutations are believed to effect enzymatic activity because the mutant protein fails to assemble into an active conformation. The ability of a protein to achieve an activ conformation is affected by a variety of intracellular protein networks including the chaperone system and the ubiquitin/proteasome system, collectively referred to as the proteostasis network. Proteostasis modulators are drugs that perturb various aspects of these networks. The preliminary data, shows that it is possible to stimulate proper folding of different mutant human CBS alleles expressed in mice by proteostasis modulating drugs. The overall goal of this proposal is to explore the interactions between proteostasis modulators and mutant alleles of CBS in a mouse model of CBS deficiency. There are three specific aims: (1) Generate and characterize new mouse models of CBS deficiency (2) Test four known proteostasis modulators for effectiveness of rescue in vivo and (3) Mechanistic studies of how proteostasis modulators effect the intracellular chaperone environment. If successful, the experiments described here could lead to novel treatments for CBS deficiency and potentially other genetic diseases associated with missense mutations.
Inborn errors of metabolism are individually rare but collectively are relatively common with an incidence of one in 1,500 individuals. In this proposal, we use cystathionine beta-synthase deficiency as a model to explore novel strategies to restore function to missense proteins by using drugs that alter the cellular folding environment. If this work is successful, it may develop into quickly translatable treatments for CBS deficiency and potentially a wide variety of other inborn errors of metabolism.