The long-term goal of our research is to understand the molecular mechanisms of hereditary retinal diseases and lay the foundation for the rational development of treatment. Many retinal diseases are caused by mutations in proteins of the visual cycle, which can easily explain photoreceptor-specific disease. However, retinal disease also results from mutations in widely expressed proteins. The photoreceptor- specific effects of these mutations are perplexing and the pathophysiological mechanisms are undefined. One such protein is inosine monophosphate dehydrogenase type 1 (IMPDH1), which catalyzes a key step in guanine nucleotide biosynthesis; mutations in IMPDH1 account for 2-3% autosomal dominant retinitis pigmentosa (adRP) cases. The effects of the IMPDH1 mutations cannot be explained by the loss of enzyme activity, which suggests that a gain/alteration of some other IMPDH1 function is responsible for disease. One alternate function is the newly discovered nucleic acid binding activity of the CBS domains of IMPDH. The adRP-causing mutations of IMPDH1 are in or near the CBS domains and we have shown that these mutations perturb nucleic acid binding. In addition, we have made the surprising discovery that IMPDH1 binds RNA and is associated with polysomes. Our observations suggest that IMPDH1 has a previously unappreciated role in RNA metabolism that is crucial for photoreceptor function. This R21 proposal describes a pilot investigation of the interactions of IMPDH1 with RNA and polysomes in photoreceptors. We hypothesize that IMPDH1 plays a role in mRNA metabolism, perhaps coordinating the translation of a subset of mRNAs, or directing mRNA localization or regulating degradation. Perturbation of any of these processes can lead to protein mislocalization, which is known to cause apoptosis of photoreceptors.
The specific aims are: (1) To determine if IMPDH1 interacts with RNA and polysome in photoreceptors. (2) To identify the RNAs that interact with IMPDH1 in photoreceptor cells. (3) To determine the effects of the adRP-causing mutations on the interaction of IMPDH1 with RNA and polysomes in photoreceptors. Relevance: IMPDH 1-mediated autosomal dominant retinitis pigmentosa accounts for 2-3% of cases. Understanding the pathophysiological mechanism for this disease will suggest new, urgently needed, strategies for therapy. In addition, this mechanism may apply to a wide variety of other hereditary diseases. Lastly, this work will provide important new insights into the biology of IMPDH, an important drug target for immunosuppressive, antiviral and cancer chemotherapy. ? ? ?
|McGrew, Dharia A; Hedstrom, Lizbeth (2012) Towards a pathological mechanism for IMPDH1-linked retinitis pigmentosa. Adv Exp Med Biol 723:539-45|
|Hoefler, B Christopher; Gollapalli, Deviprasad R; Hedstrom, Lizbeth (2011) Specific biotinylation of IMP dehydrogenase. Bioorg Med Chem Lett 21:1363-5|
|Xu, Dong; Cobb, Garrett; Spellicy, Catherine J et al. (2008) Retinal isoforms of inosine 5'-monophosphate dehydrogenase type 1 are poor nucleic acid binding proteins. Arch Biochem Biophys 472:100-4|
|Mortimer, Sarah E; Xu, Dong; McGrew, Dharia et al. (2008) IMP dehydrogenase type 1 associates with polyribosomes translating rhodopsin mRNA. J Biol Chem 283:36354-60|