Huntington’s disease is a fatal inherited disorder characterized by slow gradual personality changes, dementia, and choreiform movements. It is a progressive disease; its average onset is thirty to forty years of age, and the duration of the disease is about ten to twenty years with death as the outcome. It is known that for Huntington’s disease, there is a degeneration of cholinergic and GABAergic neurons in the basal ganglia and the cerebral cortex. The etiology of nerve cell death in Huntington’s disease is unknown. However, there is a recent hypothesis implicating defects in mitochondrial energy metabolism as the pathology of Huntington’s disease.
Huntington’s disease is an autosomal dominant disease. The genetic defect appears on the short arm of the chromosome 4, and it is an extended repetition of the three nucleotide bases (cytosine, adenine, and guanine; CAG) that code for the amino acid glutamate. This disease affects men and women equally, and it usually appears after the individuals have married and had children. The children of an affected parent have a 50% chance of inheriting the disease. With the discovery of the defective gene, it is now possible to have an accurate diagnosis before the onset of the disease.
The early indications of Huntington’s disease are not prominent; the individuals become absentminded, easily irritated, and constantly depressed. Their memory is diminished, and they lack spontaneity, initiative, and the ability to concentrate.
There are also early subtle signs of choreiform (dance-like) movements. The persons begin with "piano-playing" movements of the fingers or with slight facial twitching (Martin, 1984). The movements gradually become more uncontrollable. The speech slowly becomes incomprehensible, and swallowing is difficult. Thus, the individuals lose the ability to communicate and are improperly nourished. They are also unable to stand or walk, and are confined to bed or to a wheelchair as the disease progresses. Since no treatment is available, the ultimate result of Huntington’s disease is death.
Recent studies in choreiform movements have postulated the involvement of specific neuronal circuits in the basal ganglia. The general pathway in the basal ganglia is organized as a loop, beginning in the cerebral cortex and passing through the corpus striatum, thalamus, and back to cortex (Willard, 1993). (Fig. 1.) The circuit starts with the glutamatergic neurons from the cerebral cortex projecting to the corpus striatum. There are two pathways leaving the striatum and projecting to the internal globus pallidus. One involves GABA-ergic and substance P fibers directly innervating the internal globus pallidus; this is the direct pathway. The other, the indirect pathway, uses GABA-ergic and enkephalinergic neurons. This pathway first projects to the external globus pallidus, to the subthalamus (with GABA-ergic fibers), and then to the internal globus pallidus with glutamatergic fibers. In the normal brain, there is a balance between these two pathways; thus, the amount of input to the thalamus and the cortex is controlled.
In Huntington’s disease, the GABA-ergic and enkephalin neurons in the striatum degenerate. This leads to increased activity of the inhibitory (GABA-ergic) neurons from external globus pallidus to the subthalamus, which in turn causes a decrease in the glutamatergic (excitatory) neuronal activity on the internal globus pallidus. The result is a decreased inhibition on the thalamus, and the thalamus increases its excitatory (glutamatergic) effect on the cerebral cortex. This appears to be the cause of hyperkinesis found in Huntington’s disease.
The area affected by Huntington’s disease, the striatum (especially, the head of the caudate nucleus), receives large amount of excitatory input from the cerebral cortex and thalamus. Several studies have demonstrated that excessive intrastrial injection of EAA (excitatory amino acid) agonist (i.e., kainic acid) produces symptoms similar to those of Huntington’s. This has led to the development of "excitotoxin" theory for Huntington’s disease. In mammalian CNS, major excitatory neurotransmitters are glutamate and aspartate. Glutamate is widely distributed in the pyramidal system, and appears to be able to bind to two types of receptor, the N-methyl-D-aspartate (NMDA) and non-NMDA receptors. These receptors belong to chemically gated ion channels. The channels are permeable to Na++ and K++; the NMDA channels is also permeable to Ca++. There is also evidence for the coupling of these EAA receptors to phospholipase C, G-protein, cAMP, protein kinase, and other second messenger pathways. Thus, an increase in glutamate will alter all these coupled pathways. When glutamate is present in synaptic clefts for a prolonged period, it can cause neural cell death. One explanation offered by Rothman and Olney (1987) is that prolonged depolarization of neurons, triggered by EAA, results in influx of chloride into the cell to lower electrochemical gradients. The entry of chloride causes further Na++ and water influx, resulting in the swelling of the cells and an eventual cytolysis. The second explanation for neural cell death depends on extracellular Ca++ (Choi, 1988). The influx of extracellular Ca++, induced by NMDA-binding glutamate, increases the cytosolic concentration of Ca++. The elevation in cytosolic Ca++ may cause cell death by activating: 1) protease’s which degrade several major neuronal structural proteins; 2) phospholipases which are capable of degrading cell membrane and liberating arachidonic acid (oxidation of arachidonic acid produces oxygen free radicals); and 3) protein kinase C which leads to further increase in Ca++ influx.
The susceptibility of a neuron to excitotoxin-induced cell death is influenced by the neuron’s capacity to maintain adequate energy metabolism and ion homeostasis (Young, 1993). Some studies have shown that disturbances in energy metabolism in neurons may lead to neuronal cell death. Agents that interrupt the electron transport chain or ion transport across membranes cause cell death and develop EAA-induced excitotoxicity (Young, 1993).
The defects in neuronal energy metabolism (fig. 2) result in a decreased level of ATP. This reduced level of ATP interferes with the function of the Na++ K++ ATPase, which inhibits the depolarization of synaptic membranes after a glutamatergic stimulated depolarization. The sustained depolarization leads to prolonged opening of Ca++ channels and decreases the voltage-dependent Mg++ block of NMDA channels. These result in further influx of Ca++ through the Ca++ channels and Ca++ permeable NMDA channels, and influx of Na++. The increased flux of these two ions soon depletes the cytosolic ATP. Elevated intracellular Ca++ induces the mitochondria to take up Ca++ instead of generating ATP (Bear, Hyman and Korshetz, 1993). The decrease in ATP impairs the maintenance of neuronal membrane potential, and the increase in Ca++ results in all the destruction’s linked to excitotoxic cell injury and death as mentioned earlier.
Several evidences have indicated that there is defective energy metabolism in Huntington’s disease. Biochemical studies have shown that in Huntington’s, there is reduced pyruvate dehydrogenase activity in the basal ganglia and hippocampus (Bear, 1992). The compound, 3-nitropropionic acid, is an irreversible inhibitor of succinate dehydrogenase; hence it inhibits both the Krebs cycle and complex II of the electron transport chain. Continuous administration of this compound have resulted in proliferative growth-related changes in the dendrites of spiny neurons similar to those in Huntington’s. Lactate levels appear to be elevated in this disease. This suggests the link between the defect in energy metabolism and the Huntington’s disease (Bear et al., 1993). A recent investigation by Frim et. al. has demonstrated that nerve growth factor (NGF) can prevent striatal degeneration induced by infusions of glutamate receptor agonists. Although the mechanism of NGF-mediated protection is unknown, biologically delivered NGF protects neurons from excitotoxicity and mitochondrial blockade. This also indicates that this neurodegenerative disease is caused in part by energy depletion.
Hypotheses such as the defective mitochondrial energy metabolism not only broaden the knowledge of this illness, but they also shed some insights on the possible therapeutic approaches. If the illness is indeed caused by the impairment in energy metabolism, Beal et. al. (1993) have suggested two potential treatments. One would be to bypass the bioenergetic defect and thus prevent secondary excitotoxic damage. This implies the administration of vitamins that are coenzymes of respiratory enzymes, i.e., vitamins B. or substances that would bridge defects in the electron transport chain, i.e., vitamin C, vitamin K3 coenzyme Q10. An alternative strategy would be to use excitatory amino acid antagonists to prevent neural death. In spite of the increased knowledge of Huntington’s disease, there are still many unanswered questions. With further efforts in research, the underlying cause and the possible restoration of health may one day be apparent.
WORKS CITED:
Beal, M. Flint (1992). Does impairment of energy metabolism result in excitotoxic neuronal death in neurodegenerative illnesses? Annals of Neurology, 31 (2): pp. 119-130.
Beal, M. Flint, Hyman, Bradley T., & Koroshetz, Walter (1993). Do defects in mitochondrial energy metabolism underlie the pathology of neurodegenerative diseases? Trends in Neurological Sciences, 16 (4): pp. 125-131.
Choi, Dennis W. (1988). Glutamate neurotoxicity and diseases of the nervous system. Neuron, pp.623-632.
Prim, D. M., Simpson, J., Uhler, T. A., Short, M. P., Bossi, S. R., Breakefield, X. O., & Isacson, O. (1993). Striatal degeneration induced by mitochondrial blockade is prevented by biologically delivered NGF. Journal of Neuroscience Research, 35: pp. 452-458.
Martin, Joseph B. (1984). Huntington’s disease: New approaches to an old problem. Neurology, 34: pp. 1059-1071.
Willard, Frank H. (1993). Medical Neuroanatomy: A Problem- Oriented Manual with Annotated Atlas. Philadelphia: J. B. Lippincott Company.
Young, Anne B. (1993). Role of excitotoxins in heredito-degenerative neurologic diseases. Research Publications- Association for Research in Nervous and Mental Diseases, 71: pp. 175-189.