The Cytoskeleton and Medicine

Defects related to microtubules are specifically linked to several human diseases. One example is "immotile cilia syndrome" (Afzelius, 1979) which is caused by altered dynein and results in an inability to expel secretions from the lungs, leading to recurrent bacterial infections. Another is developmental disability in infants which is caused by abnormal MT function induced by defective MAPs (Purpura, 1982). The cytoskeleton participates in the effects of various diseases (malignancy, Alzheimer's disease, viral infections), drugs, toxins and the body's response to disease.

The pathway to understanding MT led through the disease gout, a painful swelling of joints caused by the body's response to accumulation of urate crystals. Lymphocytes and macrophages, the body's immune cells, leave the bloodstream and migrate by amoeboid locomotion towards the urate crystals which often lodge in a joint of the big toe. Gout may be precipitated by purine containing foods which are metabolized to urate. The urate crystals are not particularly harmful except for the painful inflammatory immune response they trigger. By luck, a drug called colchicine was found to be helpful in relieving the pain and tenderness. Later it was discovered that colchicine worked by depolymerizing microtubules and preventing the locomotion and engulfment behavior of the lymphocytes and macrophages.

In addition to cell migration, the cytoskeleton is clearly involved in the establishment of normal cell architecture, function, and control of cell division and growth. In malignancy, control of cell reproduction is lost and growth proceeds without regard to the needs of the organism. Cancerous cells exhibit a tendency to break away from their anchorage and set up growth elsewhere in the body. Malignant cytoskeleton is disorganized with formation of oscillating aggregates of contractile material that aids dislodgement of the cell from its anchorage, instability in chromosome number and loss of growth regulation. All these effects could be primarily cytoskeletal in origin, and Puck (1977) has proposed that malignancy is a disease of the cytoskeleton. Clearly, the cytoskeleton is involved in the expression and processes of malignant cells. In cancer, cell division goes out of control: multipolar or asymmetric mitotic spindles are commonly observed. Boveri observed in 1929 that such aberrant distribution of genetic material could result in any combination or permutation of genes, most of which would be nonviable. However, some permutations may be sufficiently viable and have the abhorrent traits of malignancy. Many other factors leading to genetic alterations can account for the same results, so the precise etiology cannot be pinpointed. Indeed, cancer is probably caused by a number of etiologies including viruses which infiltrate and usurp the genetic apparatus and cytoskeleton.

Much of our current knowledge of the cytoskeleton has been learned from experimental perturbations by toxins, poisons, or drugs. Claude Bernard said in 1875:

The poison becomes an instrument which dissociates and analyzes the special properties of different living cells; by establishing their mechanisms and causing cell death or changes in cell function we can learn indirectly much about the relation between molecular structure in the physiological process of life.

Peripheral nerve MT and axoplasmic transport are vulnerable to toxin and drug effects. Vinca alkaloids (vincristine, vinblastine) are commonly employed in battling cancer because they disrupt MT mitotic spindles as they polymerize. Because the cancerous cells are dividing so much more rapidly than normal cells, the mitotic spindle poisons are effective against malignancy. However, they can cause side effects including peripheral nerve damage by injuring MT dependent axoplasmic transport. This results in peripheral nerve damage in many patients who receive the anti-microtubule drugs. Sometimes severe neurological dysfunction limits the use of the vinca drugs. Fortunately, neither vinca alkaloids nor colchicine cross the blood brain barrier so central nervous system problems are limited.

No agents are known to selectively disrupt intermediate filaments (although 2,5 hexane dione may act in this way). In intact cells, vanadate combined with drugs that disassemble microtubules cause vimentin type intermediate filaments to collapse around the nucleus. A toxin known as beta, beta prime iminodiproprionitrile (IDPN) disrupts microtubule/neurofilament organization in axons, which results in colocalization of certain MAP II subgroups with intermediate filaments. Wisniewski and colleagues (1966) showed that injection of aluminum salts into the brain or cerebrospinal fluid of experimental animals induced marked accumulation of 10 nanometer filaments in cell bodies, dendrites and initial axon segments of large neurons. When silver stained, these accumulations superficially resemble the neurofibrillary tangles that are encountered in a number of human disease states, notably Alzheimer's disease, Parkinsonism dementia and senility. The filamentous accumulations are not precisely identical to those of the human diseases but raise interesting questions about the role of cytoskeletal proteins in these afflictions. Alzheimer's disease and related forms of senile dementia are characterized by these neurofibrillary tangles which result in various symptoms including a shortage of acetylcholine at synapses of "cholinergic" neurons. This shortage may be due to a breakdown in the cytoskeletal transport mechanisms which deliver acetylcholine precursors to the synapses. The cognitive dysfunction which characterizes the dementias is somehow related to disruption of the cytoskeleton. Other toxins whose mechanisms have been ascribed to cytoskeletal effects include hexanedione and hexacarbons, carbon disulfide, acrylamide, methylmercury, and mineral fiber asbestos.

When cells are injured by lack of oxygen, acidosis, toxins, or other causes, there is an irreversible point beyond which cell death is inevitable. Recent evidence points to a pathological elevation of cytoplasmic calcium ion as the irreversible point (Farber, 1981). The excess calcium may originate outside the cell, diffusing across damaged membranes, or may be released from cytoplasmic reservoirs including the cytoskeleton. Regardless of its source, the elevated calcium causes depolymerization of microtubules and other cytoskeletal components. The net result is a loss of cytoplasmic organization, enzyme function, and structural integrity leading to cell death. Dimethysulfoxide (DMSO) is a solvent which stabilizes polymerized microtubules, and which has been shown to preserve integrity of cells and tissues against damaging effects of radiation, low temperature, and other insults. Other compounds (taxol, poly-lysine, etc.) also fortify or preserve MT and the cytoskeleton and could be important in future therapies.

The effects of a number of other drugs may be mediated via the cytoskeleton; among these are anesthetics which cause a reversible cessation of consciousness. In the 19th century, Claude Bernard noted that an anesthetic (chloroform) inhibited "protoplasmic streaming" in slime molds, a function of the cytoskeleton. Allison and Nunn (1968) showed that sufficient concentrations of the general anesthetic halothane reversibly depolymerized MT. Sleep producing barbiturates, local anesthetics, and major tranquilizers such as thorazine also bind to brain MT. Chapter 7 will describe how anesthesia is related to inhibition of cooperative activities related to information processing in the cytoskeleton and connected membrane proteins. The future emergence of nanotechnology (Chapter 10) may permit medical intervention to be more specifically tuned to functions and dysfunctions of the cytoskeleton.

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