Systemic gene dysregulation in classical Galactosaemia: Is there a central mechanism?

Classical Galactosaemia is a rare disorder of carbohydrate metabolism caused by a deficiency of galactose-1-phosphate uridyltransferase (GALT). The disease is life-threatening in the neonate, and the only treatment option is life-long dietary restriction of galactose. However, long-term complications persist in treated patients including cognitive impairments, speech and language abnormalities and premature ovarian insufficiency in females. Microarray analysis of T-lymphocytes from treated adult patients identified systemic dysregulation of numerous gene pathways, including the glycosylation, inflammatory and inositol pathways. Analysis of gene expression in patient-derived dermal fibroblasts of patients exposed to toxic levels of galactose, with immunostaining, has further identified the susceptibility of the glycosylation gene alpha-1,2-mannosyltransferase (ALG9) and the inflammatory gene annexin A1 (ANXA1) to increased galactose concentrations. These data suggest that Galactosaemia is a multi-system disorder affecting numerous signalling pathways.

Progenitor cell types in HIV-1 infection: bioactivity and emerging targets for treatment.

HIV-1 exerts its most profound effects through destruction of the host's immune responses specifically through targeting of the T-lymphocyte populations. In addition to its primary immune target, HIV-1 also targets cells of the nervous, skeletal and vascular system. There is emerging evidence to suggest that HIV-1 may, in part at least, affect these diverse tissues by impairing the homeostatic production of terminally differentiated cells from stem and progenitor cell populations. The interaction between HIV-1 and stem cell populations may serve to underpin the diverse non-immunological effects of HIV-1. This review deals with the effect of HIV-1 infection on a number of progenitor cell types, with emphasis on delineating mechanisms of HIV's destructive effect on the body. Modification of these effects may represent novel avenues for exploration in our search for clinical interventions.

Novel roles of neuropeptide processing enzymes: EC3.4.24.15 in the neurome.

Neuropeptide processing metalloenzymes, such as angiotensin converting enzyme, neprilysin, endothelin converting enzyme, neurolysin, and EC3.4.24.15 (EP24.15), are central to the formation and degradation of bioactive peptides. We present EP24.15 as a paradigm for novel functions ascribed to these enzymes in the neurome. Although the neurome typically encompasses proteomes of the brain and central nervous system, exciting new roles of these neuropeptidases have been demonstrated in other organ systems. We discuss the involvement of EP24.15 with clinical sequelae involving the use of gonadotropin-releasing hormone (GnRH; LHRH) analogs that act as enzyme inhibitors, in vascular physiology (blood pressure regulation), and in the hematologic system (immune surveillance). Hemodynamic forces, such as cyclic strain and shear stress, on vascular cells, induce an increase in EP24.15 transcription, suggesting that neuropeptidase-mediated hydrolysis of pressor/depressor peptides is likely regulated by changes in hemodynamic force and blood pressure. Lastly, EP24.15 regulates surface expression of major histocompatibility complex Class I proteins in vivo, suggesting that EP24.15 may play an important role in maintenance of immune privilege in sites of increased endogenous expression. In these extraneural systems, regulation of both neuropeptide and other peptide substrates by neuropeptidases indicates that the influence of these enzymes may be more global than was anticipated previously, and suggests that their attributed role as neuropeptidases underestimates their physiologic actions in the neural system.