This book is one of our contemporary medical bibles. It needs no introduction; those who have frequent need of it know it very well, and those who use it less often seek it out on the library shelf when problems arise. The book is truly encyclopedic. Everything relevant discovered during the six-year intervals between publication finds its way into these pages. By today's standards, its 1,778 closely packed small-print pages are a bargain. The mutant gene is both hero and villain in this book. It is reponsible for the biochemical abnormality that results in disease, no matter how rare a given abnormality may be. By the same token, however, it is truly an experiment of nature, shedding light on fundamental metabolic sequences and biologic mechanisms. This volume, more than most, explains the contributions of the laboratory to clinical medicine. Each chapter seems to have been rewritten, so that the exciting

The Metabolic Basis Of Inherited Disease.

Lysosomal cysteine proteases: more than scavengers.

For many years apoptosis research has focused on caspases and their putative role as sole executioners of programmed cell death. Accumulating information now suggests that lysosomal cathepsins are also pivotally involved in this process, especially in pathological conditions. In particular, the role of lysosomes and lysosomal enzymes in initiation and execution of the apoptotic program has become clear in several models, to the point that the existence of a 'lysosomal pathway of apoptosis' is now generally accepted. This pathway of apoptosis can be activated by death receptors, lipid mediators, and photodamage. Lysosomal proteases can be released from the lysosomes into the cytosol, where they contribute to the apoptotic cascade upstream of mitochondria. This review focuses on the players and the molecular mechanisms involved in the lysosomal pathway of apoptosis as well as on the importance of this pathway in development and pathology.

/pdf/lysosomes-in-cell-death-45kqmblscp.pdf

Lysosomes in cell death

For years, it has been held that cathepsin D (CD) is involved in rather non-specific protein degradation in a strongly acidic milieu of lysosomes. Studies with CD knock-out mice revealed that CD is not necessary for embryonal development, but it is indispensable for postnatal tissue homeostasis. Mutation that abolishes CD enzymatic activity causes neuronal ceroid lipofuscinosis (NCL) characterized by severe neurodegeneration, developmental regression, visual loss and epilepsy in both animals and humans. In the last decade, however, an increasing number of studies demonstrated that enzymatic function of CD is not restricted solely to acidic milieu of lysosomes with important consequences in regulation of apoptosis. In addition to CD enzymatic activity, it has been shown that apoptosis is also regulated by catalytically inactive mutants of CD which suggests that CD interacts with other important molecules and influences cell signaling. Moreover, procathepsin D (pCD), secreted from cancer cells, acts as a mitogen on both cancer and stromal cells and stimulates their pro-invasive and pro-metastatic properties. Numerous studies found that pCD/CD level represents an independent prognostic factor in a variety of cancers and is therefore considered to be a potential target of anti-cancer therapy. Studies dealing with functions of cathepsin D are complicated by the fact that there are several simultaneous forms of CD in a cell—pCD, intermediate enzymatically active CD and mature heavy and light chain CD. It became evident that these forms may differently regulate the above-mentioned processes. In this article, we review the possible functions of CD and its various forms in cells and organisms during physiological and pathological conditions.

Cathepsin D--many functions of one aspartic protease.

Autodigestion of the pancreas by its own prematurely activated digestive proteases is thought to be an important event in the onset of acute pancreatitis. The mechanism responsible for the intrapancreatic activation of digestive zymogens is unknown, but a recent hypothesis predicts that a redistribution of lysosomal cathepsin B (CTSB) into a zymogen-containing subcellular compartment triggers this event. To test this hypothesis, we used CTSB-deficient mice in which the ctsb gene had been deleted by targeted disruption. After induction of experimental secretagogue‐induced pancreatitis, the trypsin activity in the pancreas of ctsb ‐/‐ animals was more than 80% lower than in ctsb +/+ animals. Pancreatic damage as indicated by serum activities of amylase and lipase, or by the extent of acinar tissue necrosis, was 50% lower in ctsb ‐/‐ animals. These experiments provide the first conclusive evidence to our knowledge that cathepsin B plays a role in intrapancreatic trypsinogen activation and the onset of acute pancreatitis. J. Clin. Invest. 106:773‐781 (2000).

/pdf/role-of-cathepsin-b-in-intracellular-trypsinogen-activation-2zoj1r7ei1.pdf

Role of cathepsin B in intracellular trypsinogen activation and the onset of acute pancreatitis

Mice deficient for the major lysosomal aspartic proteinase cathepsin D, generated by gene targeting, develop normally during the first 2 weeks, stop thriving in the third week and die in a state of anorexia at day 26 +/- 1. An atrophy of the ileal mucosa first observed in the third week progresses towards widespread intestinal necroses accompanied by thromboemboli. Thymus and spleen undergo massive destruction with fulminant loss of T and B cells. Lysosomal bulk proteolysis is maintained. These results suggest, that vital functions of cathepsin D are exerted by limited proteolysis of proteins regulating cell growth and/or tissue homeostasis, while its contribution to bulk proteolysis in lysosomes appears to be non-critical.

Mice deficient for the lysosomal proteinase cathepsin D exhibit progressive atrophy of the intestinal mucosa and profound destruction of lymphoid cells.

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Mice deficient for the lysosomal proteinase cathepsin D exhibit progressive atrophy of the intestinal mucosa and profound destruction of lymphoid cells.