Therapeutic Opportunities

Neuronal cell death in most neurodegenerative disorders, as well as in traumatic brain injury and spinal-cord damage, exhibits most of the hallmarks of apoptosis (reviewed in refs. 83-85). Limiting the extent of caspase activation in the target neuronal population may be therapeutically relevant in slowing the progression of Alzheimer's, Parkinson's, ALS, and Huntington's diseases, as well as in retinal degenerations and in the injured central nervous system (CNS) (see Chapter 14). Given that...

Alternative Cell Death In The Nervous System

Caspase-driven neuronal apoptosis strictly following the classical apoptosome pathway is best documented during development of the nervous system (49), where many superfluous cells are produced and turned over (122), and in vitro cultures of cells derived from developing brain (75). Evidence is scarce for adult neurons, and here caspase-dependent mechanisms may yield to alternative death pathways (123). Notably, a re-evaluation of cell death in caspase knockout mice showed that apoptosis is...

Bcl2 Family Of Proteins

The Bcl-2 family of proteins controls the mitochondria-initiated intrinsic apoptosis and regulates the death receptor-initiated extrinsic cell death. More than two dozen Bcl-2 family proteins have been identified in multicellular organisms examined to date (12) (see Chapter 2). On the basis of function and sequence similarity, the diverse Bcl-2 members can be grouped into three subfamilies. The anti-apoptosis subfamily, represented by Bcl-2 Bcl-XL in mammals and CED-9 in worms, inhibits...

Cellreceptor Gene Rearrangement

There are five major classes of antibodies, each with a specialized function IgG, IgM, IgA, IgD, and IgE. Each has as its basic structure two identical light chains and two identical heavy chains depending on the class, this basic tetramer has a mass of 150-190 kDa. IgA, the major antibody in secretions, is comprised of two basic tetramers held together by a J (joining) chain, and is associated with a secretory component chain. IgM has five basic tetramers and a J chain its molecular weight is...

Structure And Channel Forming Activity Of The Bcl2 Proteins

The Bcl-2 protein family contains over 20 members (see Chapter 2). The proteins have either pro-or anti-apoptotic activity and they control the mitochondrial apoptosis pathway. The three-dimentional structures are available for four Bcl-2 family proteins. Two anti-apoptotic members (Bcl-XL and Bcl-2) and two pro-apoptotic proteins, one from the multidomain subgroup (Bax) and one of the BH3 domain only group (Bid) (14-18). The overall structures of all the proteins are very similar, despite...

The Complexity Of Cell Death In Neurodegeneration

Early in the field of cell death, two distinct forms of cell death were noted necrotic, or bursting of the cell membrane, and apoptotic, wherein the cell membrane remains intact and the nuclear material is digested in a methodical manner. However, morphological analyses of both human tissue and animal models of neuronal diseases have indicated a wide range of neuronal cell-death capabilities. Although some similarities to other model systems exist, an alarming amount of disparity appears to be...

The Adaptive Immune System

We find it useful to think of the immune system as a chemical sense organ, similar to the more familiar senses of taste and smell. They all function to identify novel materials, in a sense, which we then arrange to remove or inactivate. The immune system comes into play once foreign materials have achieved access to the interior. It is our cellular and molecular surveillance organ, and must not only distinguish between self and non-self, but also arrange for the inactivation, destruction, and...

Trail

The TNF family of proteins (tumor necrosis factor-a TNF-a , FasL, and TNF-related apoptosis-inducing ligand TRAIL ) are cytokines with multiple physiological roles. The ability of this family to induce apoptosis has been well-characterized in inflammatory and immune responses (4,5). This has led many investigators to assess the anti-cancer therapeutic capability of these molecules (4,6). However, systemic administration of TNF-a and FasL has proven to be too toxic for therapeutic use (7,8). A...

Regulation Of Bcl2 Family Proteins

Because of the potent effects of Bcl-2 family proteins on the balance of life and death, cells impose strict regulations on the expression and activity of these molecules. Whereas certain antideath or prodeath molecules are expressed constitutively in cells, others are expressed only following death stimuli. This is particularly true for a number of pro-apoptosis molecules. For example, DNA damage can induce the expression of Noxa and PUMA in a p53-dependent manner (59-61). Upregulation of...

Pcd Can Take Many Forms

If one keeps to the strict morphological criteria of apoptosis, including the geometrical shape of chromatin after its condensation (Fig. 2), caspases seem indispensable for apoptosis. However, there are many forms of apoptosis-like PCD where the chromatin condenses to less geometric shapes, and where phagocytosis markers on the plasma membrane are displayed before cell lysis. An array of well-characterized cell-death models occurring in the absence of caspase activation falls into this...

Pcd In Plants

Plants are simple multicellular organisms that vary considerably from animals. On the cellular level, plant cells contain rigid cell walls composed mainly of cellulose, a large vacuole that participates in many molecular and biochemical processes, and a specialized organelle responsible for conducting photosynthesis, i.e., the chloroplast. Plants do not have an immune system similar to animals, but are capable of controlling and coordinating a large array of defenses when attacked by pathogens....