The role of hypothalamic RNA binding protein Caprin2 in osmoregulatory dysfunction in old age

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By 2050, 25% of the population will be over 65. Whilst this dramatic increase in lifespan should be celebrated, the resultant demographic change represents a major challenge. This is because wellbeing and health in old age has not improved proportionally with longevity. The reasons why bodily systems deteriorate in the elderly is not well understood. However, there is growing evidence that brain dysfunction is involved in a wide range of chronic conditions of old age. For example, disorders of fluid balance are evident in a substantial proportion of elderly patients admitted to hospital, and dehydration is a frequent cause of morbidity and mortality in old people. A specialised part of the brain called the hypothalamus controls the excretion of water through the production of a hormone called vasopressin (AVP) that tells the kidney to conserve water. AVP is a protein hormone that is encoded by the corresponding AVP gene. When an animal becomes dehydrated, AVP is released from the hypothalamus and there is thus a need to make more. Twenty five years ago, we showed that the expression of the AVP gene is hence activated, and more messenger RNA (mRNA) is made. At the same time, the AVP mRNA undergoes an unusual modification; the string of adenine (A) residues at the end of the mRNA - the so-called poly(A) tail - increases in length from around 200 to 400 residues. Importantly, we have recently shown that the AVP mRNA poly(A) tail length increases with age in rats. Using methods that allow is to simultaneously describe the expression of all genes, we identified another gene, called Caprin2, an RNA binding protein, as being increased in expression in the hypothalamus following dehydration. There are over a thousand RNA binding proteins, but their physiological roles are not understood. We have shown that Caprin2 has a pivotal role in the brain mechanisms that control fluid balance. We showed that Caprin2 binds to the AVP mRNA and mediates the increase in poly(A) tail length. Importantly, when we knockdown expression of Caprin2 in the hypothalamus, we alter the response to a dehydrating stimulus - more AVP is released into the blood, suggesting that the normal function of Caprin2 is to inhibit this in some way. Importantly, we have shown that old age in rats results in an increase in Caprin2 expression, in parallel with the increase in AVP mRNA poly(A) tail length. We then used unbiased mathematical tools that use global gene expression data to predict gene interactions. We tested this gene network and validated regulatory interactions between Caprin2 and the genes encoding the neuropeptide dynorphin, haemoglobin-beta and the receptor Opsin-3. Or aims are now to decipher the detailed molecular mechanisms by which Caprin2 affects a network of gene expression in the hypothalamus, and hence regulates the crucial hormonal and physiological processes that govern salt and water homeostasis. Further, we will test the hypothesis that changes in Caprin2 activity underlie, at least in part, the homeostatic dysfunction of old age. These unique studies will tell us about the mechanisms by which an RNA binding protein affect gene expression and hence mediate physiological stability, and how this goes wrong in old age.