Cleavage of huntingtin (htt) has been characterized in vitro, and accumulation of caspase cleavage fragments represents an early pathological change in brains of Huntington's disease (HD) patients. However, the relationship between htt proteolysis and the pathogenesis of HD is unknown. To determine whether caspase cleavage of htt is a key event in the neuronal dysfunction and selective neurodegeneration in HD, we generated YAC mice expressing caspase-3- and caspase-6-resistant mutant htt. Mice expressing mutant htt, resistant to cleavage by caspase-6 but not caspase-3, maintain normal neuronal function and do not develop striatal neurodegeneration. Furthermore, caspase-6-resistant mutant htt mice are protected against neurotoxicity induced by multiple stressors including NMDA, quinolinic acid (QA), and staurosporine. These results are consistent with proteolysis of htt at the caspase-6 cleavage site being an important event in mediating neuronal dysfunction and neurodegeneration and highlight the significant role of htt proteolysis and excitotoxicity in HD.

Colostrum and milk provide a complete diet for the neonate. In ruminants, colostrum is also the sole source of initial acquired immunity for the offspring. Milk therefore plays an important role in mammalian host defense. In colostrum, the concentration of immunoglobulins is particularly high, with IgG being the major immunoglobulin class present in ruminant milk, in contrast to IgA being the major immunoglobulin present in human milk. Immunoglobulins are transported into mammary secretions via specialized receptors. In addition to immunoglobulins, both colostrum and milk contain viable cells, including neutrophils and macrophages, which secrete a range of immune-related components into milk. These include cytokines and antimicrobial proteins and peptides, such as lactoferrin, defensins, and cathelicidins. Mammary epithelial cells themselves also contribute to the host defense by secreting a range of innate immune effector molecules. A detailed understanding of these proteins and peptides offers great potential to add value to the dairy industry. This is demonstrated by the wide-ranging commercial applications of lactoferrin derived from bovine milk. Knowledge of the immune function of milk, in particular, how the gland responds to pathogens, can be used to boost the concentrations of immune factors in milk through farm management practices and vaccination protocols. The latter approach is currently being used to maximize yields of bovine milk-derived IgA directed at specific antigens for therapeutic and prophylactic use. Increasingly sophisticated proteomics technologies are being applied to identify and characterize the functions of the minor components of milk. An overview is presented of the immune factors in colostrum and milk as well as the results of research aimed at realizing this untapped value in milk.

In neurons, posttranslational modification by palmitate regulates the trafficking and function of signaling molecules, neurotransmitter receptors, and associated synaptic scaffolding proteins. However, the enzymatic machinery involved in protein palmitoylation has remained elusive. Here, using biochemical assays, we show that huntingtin (htt) interacting protein, HIP14, is a neuronal palmitoyl transferase (PAT). HIP14 shows remarkable substrate specificity for neuronal proteins, including SNAP-25, PSD-95, GAD65, synaptotagmin I, and htt. Conversely, HIP14 is catalytically invariant toward paralemmin and synaptotagmin VII. Exogenous HIP14 enhances palmitoylation-dependent vesicular trafficking of several acylated proteins in both heterologous cells and neurons. Moreover, interference with endogenous expression of HIP14 reduces clustering of PSD-95 and GAD65 in neurons. These findings define HIP14 as a mammalian palmitoyl transferase involved in the palmitoylation and trafficking of multiple neuronal proteins.

The mammalian ribonucleaseA family comprises a large group of structurally similar proteins which are secreted by a range of tissues and immune cells. Their physiological role is unclear. It has been suggested that some of these RNases contribute to host defence, notably eosinophil-derived neurotoxin, eosinophil cationic protein, eosinophil-associated RNases, RNase4, angiogenin (RNase5), RNase7, RNase8 and bovine seminal RNase. This review summarises data supporting the involvement of these proteins in host defence, focusing on their antimicrobial, cytotoxic and immunomodulatory activities. The extent to which the data support possible mechanisms of action for these proteins is discussed. This compilation of findings and current hypotheses on the physiological role of these RNases will provide a stimulus for further research and development of ideas on the contribution of the RNases to host defence.