The RP 10 form of autosomal dominant retinitis pigmentosa (adRP) is caused by mutations in the widely expressed protein inosine 5′-monophosphate dehydrogenase type 1 (IMPDH1). These mutations have no effect on the enzymatic activity of IMPDH1, but do perturb the association of IMPDH1 with nucleic acids. Two newly discovered retinal-specific isoforms, IMPDH1(546) and IMPDH1 (595) (595) is also similar to the canonical IMPDH1 and unaffected by the D226N mutation. However, unlike the canonical IMPDH1, the retinal specific isoforms do not bind significant fractions of a random pool of oligonucleotides. This observation indicates that the C-terminal extension unique to the retinal isoforms blocks the nucleic acid binding site of the IMPDH1, and thus uniquely regulates protein function within photoreceptors.
Retinitis pigmentosa (RP) is a disease characterized by its vast heterogeneity. Many genes are associated with RP, and the disease causing mutations identified in these genes are even more numerous. To date there are 15 genes that cause autosomal dominant RP (adRP) alone. The role of some of these genes, while complex and not completely understood, is somewhat intuitive in that they are involved in pathways such as phototransduction. However, the role of other genes in retinal disease is not as predictable due to their ubiquitous function and/or expression. One such gene is inosine monophosphate dehydrogenase 1 (IMPDH1) IMPDH1 is a gene involved in de novo purine synthesis and is ubiquitously expressed. IMPDH1 mutations account for 2% of all adRP cases and are a rare cause of Leiber Congenital Amaurosis. Despite its ubiquitous expression missense mutations in this gene cause only retinal degeneration. This paradox of tissue specific disease in the presence of ubiquitous expression has only recently begun to be explained. We have shown in a recent study that novel retinal isoforms of IMPDH1 exist and may account for the tissue specificity of disease. We have gone on to characterize these retinal isoforms both in our laboratory and in collaboration with Dr. Lizbeth Hedstrom’s laboratory at Brandeis University (Waltham, MA) in order to understand more about them. We believe that through clarifying the mechanism of disease in RP10 we will be equipped to consider treatment options for this disease.
Calpains and caspases are ubiquitous cysteine proteases that are associated with a variety of cellular pathways. Calpains are involved in processes such as long term potentiation, cell motility and apoptosis, and have been shown to cleave non-erythroid (brain) α- and β-spectrin and erythroid β-spectrin. The cleavage of erythroid α-spectrin by calpain has not been reported. Caspases play an important role in the initiation and execution of apoptosis, and have been shown to cleave non-erythroid but not erythroid spectrin. We have studied the effect of spectrin fragments on calpain and caspase activities. The erythroid and non-erythroid spectrin fragments used were from the N-terminal region of α-spectrin, and C-terminal region of β-spectrin, both consisting of regions involved in spectrin tetramer formation. We observed that the all spectrin fragments exhibited a concentration-dependent inhibitory effect on calpain, but not caspase activity. It is clear that additional studies are warranted to determine the physiological significance of calpain inhibition by spectrin fragments. Our findings suggest that calpain activity is modulated by the presence of spectrin partial domains at the tetramerization site. It is not clear whether the inhibitory effect is substrate specific or is a general effect. Further studies of this inhibitory effect may lead to the identification and development of new therapeutic agents specifically for calpains, but not for caspases. Proteins/peptides with a coiled coil helical conformation should be studied for potential inhibitory effects on calpain activity.
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