Other Potential Roles As A Neuropeptidase

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The fact that 24.15 cleaves Somatostatin, Substance P, Neurotensin, Neoendorphins, Dynorphin, Metorphinamide, GnRH, and other neuropeptides is striking. Even more striking are the roles of these peptides in many degenerative diseases including AD. Somatostatin, for example, has been shown to be significantly deficient in AD83. It is important for memory and experimental lowering triggers a severe impairment of memory71. Therefore, if connections can be drawn between these many disparate peptides acted upon by 24.15, they can lead to functional clues. These insights may indicate the specific overarching role that 24.15 is playing. We expect this function to be critical to both normal and pathologic physiology. We will take a brief look here at some of the more interesting of these connections.

Pain and Analgesia

It has been noted already that 24.15 acts upon a - and P-Neoendorphin, Metorphinamide, and Dynorphin A. It has also been shown that by selectively inhibiting the metallopeptidase, rats display an increased pain threshold and tail-flick latency84a as would be expected. These effects can be blocked by administration of the opiate antagonist, naloxone. So it may be assumed, by this alone, that 24.15 plays an important role in analgesia. In the degradation of these peptides by 24.15, however, the enzyme in turn generates both Met-and Leu-enkephalins. These latter two peptides display analgesic properties of their own including antinociception84b. These different opioids are suspected of mediating different types of analgesic effects in the brain. Because 24.15 is capable of converting one type of opioid peptide into another, it may be in part responsible for tailoring the analgesic response to match the organism's need.

There is greater significance to 24.15 than its action on opioid peptides alone however, for the enzyme acts on at least four other distinct analgesia-mediating pathways. The Neurotensin/Neuromedin system and the Orphanin system both point to 24.15 as a major regulator. Similarly, Bradykinin and Substance P mediate pain sensation and processes and are effectively degraded by the same enzyme32,85. What might 24.15 be doing that it is so intimately linked to at least 5 different pain and analgesia systems? Clearly, it begs the question whether some or even all of these pathways are linked. It is possible that regulation of this single peptidase could be in part responsible for a coordinated analgesic response.

It is also not unreasonable to suggest that these peptides may be intimately linked with learning and memory processes. Therefore it may be a foregone conclusion that 24.15 plays a unique role in mediating these learning and memory functions. Looking at its role in AP-clearance may be enough in itself to make this case. Soluble AP has been seen to be associated with synaptic loss86. Additionally, it takes only a small leap to argue that a misregulation or dysfunction of this enzyme could be a serious contributing factor to memory loss, learning difficulties, and neurodegeneration. Estrogen, which is under the influence of 24.15 as discussed below, has a clear role in learning as well87. Or, on the other side of the coin, that 24.15 could be a valuable target for the remedy of these ailing systems. Remarkably, little work has explored these possibilities.

Hormonal Implications

Prolyl Endopeptidase and 24.15 have been long known to be the two principal post-translational regulators of Gonadotropin Releasing Hormone (GnRH.). This critical peptide is responsible for determining the secretion of Luteinizing Hormone (LH) and Follicle Stimulating Hormone (FSH). LH and FSH, in turn, determine the pattern of secretion of all the major sex hormones of the body including estrogen, progesterone, testosterone and their derivatives. For this reason GnFw has been called the "Master Hormone". The involvement of 24.15 here is compelling for a variety of other indications surrounding the enzyme in both a reproductive as well as neural sense.

24.15 is routinely seen at highest concentrations in the testis. Why? It is unclear, but it is known that both enkephalins and endorphins (generated and degraded by 24.15, respectively) are potent activators of smooth muscle tone in the male reproductive tract.

Similarly, Substance P (also degraded by 24.15) has been shown to have a role in increasing contractility of vas deferens smooth muscle88. In addition, 24.15 (studied then as Pz-peptidase), was shown to double in activity in uterine tissue during the course of gestation and then double again during labor.

It has been long known that estradiol plays a very large role in neural remodeling and cognition. Studies of post-menopausal women who are given estradiol exogenously routinely fare better on tests for cognitive function and decline. Pertinent to our own research in AD, women who received estradiol post-menopausally demonstrated an increased age of disease onset and a slower rate of progression towards dementia89. The role of estradiol is still unclear but the effect is pronounced.

One very interesting side note to the possible involvement of 24.15 in a hormonally regulatory role is found with female athletes. High performance female athletes frequently experience amenorrhea90. This is believed to result from a lack of GnRH pulsatility.91 GnRH pulsatility has been suggested to be mediated by an autofeedback loop whereby the GnRH breakdown products (after Prolyl Endopeptidase and 24.15 processing) may act to modulate GnRH release92. Endorphin and enkephalin release are pronounced in these types of activities. Therefore 24.15 is in a key position on each side of the issue. Does the athleticism and toll on the body result in a change in 24.15 levels such that greater enkephalins are produced and consequently GnRH is shut down? Or is it that the enkephalin/endorphin-release trigger a 24.15 response that reacts consequently on GnRH This is also unknown. But here we see as well that the enzyme is uniquely poised to be a key player in this physiology.

Inflammation role

Inflammation has been repeatedly proven to be a critical player in a number of neurodegenerative diseases, including Alzheimer's disease, Parkinson's disease, Amyotrophic Lateral Sclerosis, Multiple Sclerosis, and many others. Strangely, this diverse metallopeptidase 24.15 has a number of potential connections to the role of inflammation as well.

Substance P, Neurotensin, endorphins93 and Bradykinin32 (all degraded by 24.15 as discussed) are primary mediators of the inflammatory response. Substance P induces cytokine release and activates mast cells93a. Neurotensin has been seen to bind to peritioneal macrophages and modulate phagocytic activation93. Enkephalins and endorphins stimulate interferon release, chemotaxis, superoxide production, antibody-dependent cytotoxicity and a variety of other functions93. Bradykinin is markedly increased in human skin during severe inflammation. It induces vasodilation, prostacyclin synthesis, and leads to intracellular calcium influx32. Also at least one paper reported that PGE2 upregulates 24.1594. It is known that chronic users of non-steroidal anti-inflammatory drugs (NSAIDS) are consistently seen to have a reduced incidence of AD, and a consequent diminished rate of progression to dementia. Therefore, the effect of PGE2 on 24.15 (which is in turn inhibited by NSAIDS) is another possible connection that travels hand in hand with the degradation of the other neuropeptides that are also strong inflammatory mediators.

Most intriguing of all, however, is the recent 1999 data by Silva et al. In their studies of the potential role of 24.15 in antigen presentation, this group performed an experiment theoretically similar to our own with Alzheimer's disease. In one series of experiments they used a liposome transfection method to transfer 24.15 directly into T-cells. T-cells which were transfected with the enzyme had a diminished doubling time (ie divided more rapidly), whereas introduction of 24.15 specific inhibitors had the opposite effect. They also showed that the 24.15-containing immune cells were more efficient at killing a mycobacterium-containing macrophage. Again, the 24.15 inhibitor blocked this effect61. This correlates very well to our own work where we see neuroblastoma cells transfected with 24.15 antisense RNA grow at a significantly reduced rate compared to over-expressing cells35. In another set of experiments published side by side with this one they showed that 24.15 bound tightly to a set of randomly generated peptides23. However, the enzyme only actually cleaved a very small fraction of them. This led the group to hypothesize that 24.15 may be instrumental in trafficking these peptides. Instead of cleaving them, it acts to protect the majority of them from cleavage. The antigens are transported intact to the antigen presenting machinery of the cell. Rather than modifying the post-proteasomally processed peptides to make them suitable for presentation, 24.15 may somehow select the appropriate antigens and then protect them on route to the cell surface. Other work in our own laboratory with the protease Bleomycin Hydrolase (BH) has suggested that both BH and 24.15 may be considered as "chaperases". Bh and 24.15 both serve on the one hand as a protease or peptidase, and on the other hand with the ability to act as a chaperone to a protein or peptide, respectively95.

The specifically coordinated role of 24.15 in inflammation and antigen presentation is being actively pursued. Obviously much work here remains and speculation still dominates the field.

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