Saturday 4 February 2006
Abnormalities of the cytoskeleton underlie a variety of pathologic states.
The normal cytoskeleton
The cytoskeleton consists of microtubules (20 to 25 nm in diameter), thin actin filaments (6 to 8 nm), thick myosin filaments (15 nm), and various classes of intermediate filaments (10 nm). Several other nonpolymerized and nonfilamentous forms of contractile proteins also exist.
Cytoskeletal abnormalities may be reflected by: (1) defects in cell function, such as cell locomotion and intracellular organelle movements, and (2) in some instances by intracellular accumulations of fibrillar material. Only a few examples are cited.
thin filaments. Thin filaments are composed of actin, myosin, and their associated regulatory proteins. Functioning thin filaments are essential for various stages of leukocyte movement or the ability of such cells to perform phagocytosis adequately. Some drugs and toxins target actin filaments and thus affect these processes. For example, cytochalasin B prevents polymerization of actin filaments, and phalloidin, a toxin of the mushroom Amanita phalloides, also binds actin filaments.
Defects in the organization of microtubules can inhibit sperm motility, causing male sterility, and can immobilize the cilia of respiratory epithelium, causing interference with the ability of this epithelium to clear inhaled bacteria, leading to bronchiectasis (Kartagener’s syndrome, or the immotile cilia syndrome; Chapter 15). Microtubules, like microfilaments, are essential for leukocyte migration and phagocytosis. Drugs such as colchicine bind to tubulin and prevent the assembly of microtubules. The drug is used in acute attacks of gout to prevent leukocyte migration and phagocytosis in response to deposition of urate crystals. Microtubules are an essential component of the mitotic spindle, which is required for cell division. Drugs that bind to microtubules (e.g., vinca alkaloids) can be antiproliferative and therefore act as antitumor agents.
These components provide a flexible intracellular scaffold that organizes the cytoplasm and resists forces applied to the cell.
The intermediate filaments are divided into five classes, including keratin filaments (characteristic of epithelial cells), neurofilaments (neurons), desmin filaments (muscle cells), vimentin filaments (connective tissue cells), and glial filaments (astrocytes).
Accumulations of keratin filaments and neurofilaments are associated with certain types of cell injury.
For example, the Mallory body, or "alcoholic hyalin," is an eosinophilic intracytoplasmic inclusion in liver cells that is characteristic of alcoholic liver disease,73 although it can be present in other conditions.
Such inclusions are composed predominantly of keratin intermediate filaments.
In the nervous system, neurofilaments are present in the axon, where they provide structural support. The neurofibrillary tangle found in the brain in Alzheimer disease contains microtubule-associated proteins and neurofilaments, a reflection of a disrupted neuronal cytoskeleton.
Mutations in intermediate filament genes cause multiple human disorders, including myopathies, neurologic diseases, and skin diseases.
Much of the emphasis on the functions of the cytoskeleton has been on its mechanical role, in maintaining cellular architecture and in cell attachment and locomotion.
It has recently been appreciated that cytoskeletal proteins are linked to many cellular receptors, such as lymphocyte receptors for antigens, and are active participants in signal transduction by these receptors.
Therefore, defects in the links between receptors and cytoskeletal proteins may affect many cellular responses. The Wiskott-Aldrich syndrome is an inherited disease characterized by eczema, platelet abnormalities, and immune deficiency.
The protein that is mutated in this disease is involved in linking lymphocyte antigen receptors (and perhaps other receptors) to the cytoskeleton, and defects in the protein interfere with diverse cellular responses.