Anatomical Pathology in Huntington's Disease
The Mutant Gene and Protein of Huntington's Disease
Localization of Huntingtin
Mechanisms of Neuronal Degeneration
Treatments and Tests for Huntington's Disease
Huntington’s disease (HD), a progressive neurodegenerative disorder, reveals itself through chorea: quick, jerky, and purposeless movements. This inherited autosomal dominant disease is associated with a significant and uniform decline of cognitive functions and abnormal involuntary and voluntary movements. A preferential loss of neurons occurs in the neostriatum and the cortex (Cudkowicz and Kowall, 1990). Abnormal motor behavior results from this selective degeneration of the striatum in the basal ganglia, especially the caudate nucleus (Figure 1).
Figure 1: Brain section of a patient with Huntington's disease.
The ventricles are enlarged and the caudate nucleus is atrophied.
(Permission for use of picture pending; taken from The National Center
for Biotechnology Information; click on the picture to be linked.)
Onset of the disease occurs between 35 and 44 years of age. The median survival time of individuals suffering with HD is 15-18 years. During the early stages of this disorder, individuals maintain their jobs and perform daily activities. The involuntary spasmodic movement of muscles in chorea occurs throughout the body. These uncontrollable movements are always present in states of arousal and increase with stress. Almost 90% of the HD population suffers from this symptom, which increases in intensity during the first 10 years of the disease. Other dysfunctions of movement are hyperreflexia, bradykinesia (slowness of movement), dysarthria (difficulty with voluntary activity), dystonia (ongoing contraction or spasm in a group of muscles), and oculomotor disturbances of saccadic movement and gaze fixation. Subtle changes in coordination also occur.
In later stages, choreic movements increase, while voluntary
activity and swallowing are more difficult (dysarthria and dysphagia).
Individuals lose social inhibitions and present aggressive behaviors.
Although HD patients at this stage maintain some dignity, they cannot retain
their occupations and depend upon others. Behavioral problems decrease
during the final stages of the disease. Patients are severely disabled,
mute, incontinent, and forced to remain in bed. End stage HD patients
require full time care (Harper, 1996).
HD affects the basal ganglia, large masses of gray matter located deep within the cerebral hemispheres that regulate and coordinate cortically originated movement. The corpus striatum includes the globus pallidus and the striatum, which contains the caudate nucleus and the putamen. The caudate nucleus sends projections to the putamen, which then projects to the globus pallidus. The pear shaped head of the caudate nucleus lies next to the inferior border of the anterior horn of the lateral ventricle, while its tail runs parallel to the roof of the temporal horn of the lateral ventricle (Figure 2).
5. Tail of caudate nucleus 6. Connecting piece between lentiform nucleus and taiI of caudate
nucleus 7. Amygdaloid body 8. Anterior commissure 9. Stria terminalis 10. Internal capsule
11. Cut surface of basis pedunculi
Figure 2: The right cerebral hemisphere from the
The large, convex gray matter that composes the putamen lies lateral to and beneath the insular cortex (Figure 3). The internal capsule, sheets of myelinated fibers, runs between the caudate nucleus and the putamen and conveys the striped appearance of the corpus striatum (Figure 4). Afferent projections from the thalamus synapse with the caudate nucleus. The lenticular nucleus receives some input from the substantia nigra. The caudate nucleus and the putamen receive the major input to the basal ganglia.
4. Sagittal stratum 5. Anterior commissure
Figure 3: The right cerebral hemisphere from the
6. Olfactory tract 7. Straight gyrus 8. Anterior (rostral) commissure 9. Optic chiasma
10. Optic nerve
Figure 4: The left hemisphere from the lateral
The globus pallidus and the putamen, two structures separated by the external medullary lamina, form the lenticular nucleus. Numerous myelinated fibers form the small, triangular body of the globus pallidus (Figure 4). A medullary lamina divides the globus pallidus into a medial and a lateral portion. The lateral portion receives enkephalin-producing neurons, while the medial portion receives substance P producing neurons. This nucleus projects the major outflow of the basal ganglia. These interconnections confer control of movement and posture (Waxman, 2000).
In HD, binding at serotonin and muscarinic cholinergic
receptors reduces by 50% in the caudate putamen, but is normal in the cerebral
cortex (Enna, et al., 1976). Atrophy of the striatum is due to degeneration
of its medium-sized spiny neurons and causes problems with voluntary movement
(Figures 1 and 2). Neurons that project to the lateral globus pallidus
are preferentially lost. Although the lateral portion of the globus
pallidus is more severely affected than the medial portion during the early
and middle phases of HD, all areas of the striatum are depleted in advanced
stages (Reiner et al., 1988; Sapp et al., 1995). The
cannabinoid receptors of striatal nerve terminals in lateral GP are lost
more than those of the medial GP (Richfield and Herkenham, 1994).
These abnormalities produce the clinical manifestations of HD.
In 1993, the Huntington’s Disease Collaborative Research Group used positional cloning to isolate a mutant gene that causes HD. The HD gene, also called IT15 for important transcript 15, is located on chromosome 4 at locus p16.3 (Figure 4). The mutant DNA sequence contains an unstable and expanded repeat of the nucleotides cytosine, adenine, and guanine (CAG).
Figure 5: Human Chromosome 4
(Permission for use of picture pending; taken from The National Center
for Biotechnology Information; click on the picture to be linked.)
A normal allele for gene IT15 contains 10-26 CAG repeats. Individuals with 27-35 repeats fall into the intermediate range, and their children are at risk for HD. The abnormal range varies between 36-121 alleles; individuals at the bottom of this range may or may not develop symptoms of HD. Expansions greater than 60 repeats result in juvenile onset, while those between 40 and 55 repeats induce adult onset (Andrew et al., 1997). In a study of families from various ethnic backgrounds, all 75 families afflicted with HD contained a form of the extended (CAG)n trinucleotide repeat at the p16.3 locus (Huntington’s Disease Collaborative Research Group, 1993).
Individuals who lack the HD gene on both chromosomes present no symptoms of HD (Albin & Tagle, 1995). This finding suggests that the mutation establishes a gain of function, which results in cell death. For example, a female with a breakpoint between exons had a disrupted HD gene. However, her phenotype was normal. Inactivation of the gene does not cause HD. This result argues that the dominant HD mutation creates a new property for the mRNA or alters an interaction at the protein level (Leeflang et al., 1999).
In order to identify the normal function of the HD gene, Nasir et al. deleted an exon of the murine HD homolog (Hdh) through homologous recombination (1995). Blastula homozygous for the targeted disruption died before embryonic day 8.5. Gastrulation was not initiated and somites were not formed. Although heterozygotes survived, they suffered from severe cognitive deficits. Their motor activity increased. Neurons of the subthalamic nucleus of heterozygotes degenerated. Therefore, the murine homolog of the HD gene is essential for development of the embryo, and plays a role in the normal function of the basal ganglia.
Hoogeveen et al. synthesized oligopeptides to model translation of the carboxy-terminal end of the IT15 gene (1993). Lymphoblastoid cells of normal and HD individuals were co-transfected with these short peptides. Polyclonal antibodies specific for epitopes on the oligopeptides bound to a protein, huntingtin. Huntington’s normal form contains 3144 residues and weighs 330 kDa. No proteins share homologous sequences with huntingtin. The molecular mass and localization of the protein was the same in normal and HD cells.
Eight other CNS diseases are associated with unrelated
proteins that all contain expanded polyglutamine sequences. Since
these proteins share no other homology, the repeats are the primary cause
of the disorders. Transgenes in mice that express extended polyglutamine
tracts induce neurological disease (Mangiarini et al., 1996).
Longer repeats are associated with earlier onset and increased severity
of these diseases (Duyao et al., 1993).
Localization of the HD protein shows a wide expression of this product; however, patterns of expression fail to correlate with patterns of neuropathology. Trottier, Biancalana, and Mandel ran western blots of many cell lines with monoclonal antibodies against different epitopes of the huntingtin protein (1994). Huntingtin was detected in various human cell lines. In HD cell lines, the antibodies bound to two proteins, the normal and mutant forms of huntingtin. Mutant huntingtin is located in normal and affected brain regions of HD individuals (Aronin, 1995).
The presence of normal and mutant huntingtin was observed in immunohistochemical studies examining lymphoblastoid cell lines in cases of HD heterozygotes with juvenile onset (Gutekanst, Levey, Heilman, Whaley, Yi, Nash, Rees, Madden, & Hersch, 1995). Increasing expansions of the trinucleotide repeat correlated with lower levels of mutant protein. Immunocytochemistry of the brain of these HD individuals showed the highest levels of huntingtin in the largest neurons. The human striatum contains a patch-like distribution of huntingtin.
Expression of the IT15 gene occurs mainly in neurons (Dure,
1994). In situ hybridization of normal human fetal and adult brains
with probes for IT15 showed signals of transcription throughout the brain
except in areas of the germinal matrix and white matter. Huntingtin
is expressed equally in all types of neurons. It is found within
the perikarya and nerve endings of neurons, neuropils, and varicositites.
Huntingtin is localized subcellularly in the cytoplasm and the nucleus
(De Rooij, Dorsman, Smoor, Den Dunnen, & Van Ommen, 1996). This cytosolic
protein is located primarily in somatodendritic regions. In heterozygotes,
the mutant protein is synthesized and transported with the normal protein
to the nerve endings. Huntingtin translocates to the nucleus in neurons.
Microtubules and synaptic vesicles are associated with huntingtin.
The HD mutation may affect cytoskeletal anchoring or transport of mitochondria
Difiglia et al. suggest two mechanisms by which huntingtin induces neurodegeneration (1997). Mutant huntingtin may react with other proteins and change their function. Most likely, however, fragments of this abnormal protein homodimerize or heterodimerize to form large, insoluble aggregates of protein within the nucleus, intranuclear inclusions (Perutz, 1996; Kahlem, Terre, Green, and Dijan, 1996). Kahlem, Green and Dijan observed transglutaminase (TGase) activity on huntingtin in vitro (1998). The extended polyglutamine domains of huntingtin form a substrate for TGase; TGase activity and the length of the polyglutamine sequence are positively correlated (Kahlem et al., 1996; Narain, Wyttenbach, Rankin, Furlong, and Rubinsztein, 1999). TGase catalyzes the formation of glutamyl-lysine bonds. These glutamine residues cross-link within and between various proteins; this crosslinking induces the formation of rigid supramolecular structures. Cariello et al. measured TGase activity in lymphocytes (1996). This enzymatic activity was significantly higher in 25% of the lymphocytes of HD patients than in normal controls. Normally, TGase activity decreases with age; in HD patients, TGase activity increases with age.
Huntingtin aggregates form through a nucleation dependent polymerization. Preformed fibrils initiate in vitro aggregation of huntingtin (Scherzinger et al., 1999). Aggregation depends on polyglutamine-repeat length and protein concentration. The presence of wild type huntingtin does not enhance or interfere with aggregation. Rate of aggregation depends on the number transglutamine repeats (Narain et al., 1999).
Sandou, Finkbeiner, Devys, and Greenberg developed a cellular model of HD to investigate the effects of huntingtin on neurons (1998). When cultured striatal neurons were transfected with mutant huntingtin, they were induced into an apoptotic state. Both neurotrophic factors and antiapoptotic compounds inhibited apoptosis from occurring. When mutant huntingtin was blocked from entering the nucleus, neurons did not degenerate and intranuclear inclusions did not form. Presence of inclusions does not correlate with the degree of apoptotic death induced by HD. The inability to form inclusions in these striatal cells resulted in an increase of cellular death induced by mutant huntingtin.
Huntingtin is involved in processes that counterbalance normal apoptotic pathways (Zeitlin, Liu, Chapman, Papaioannou, and Efstratiadis, 1995). Inappropriate modes of apoptosis may result in the neurodegeneration seen in HD (Portera-Cailliau, Hedreen, Price, & Koliatos, 1995). Apopain is a human protease death gene product, with a key role in events that lead to cell death. This enzyme cleaves huntingtin. Apoptotic extracts show that rates of cleavage multiply with a corresponding increase in the length of the polyglutamine tract of huntingtin (Goldberg et al., 1996).
An amino-terminal fragment of mutant huntingtin localizes to toxic neuronal intranuclear inclusions and dystrophic neurites in cortex and striatum of HD individuals (Difiglia et al., 1997). Accumulation of huntingtin within these structures is influenced by polyglutamine length. The protein ubiquitin labels proteins for disposal by intracellular proteolysis. Ubiquitin is found within intranuclear inclusions. Huntingtin, however, resists removal from the inclusions. Davies et al., created mice transgenic for exon 1 of HD with 41trinucleotide repeats. These mice developed neuronal intranuclear inclusions that contained huntingtin and ubiquitin, and later developed a neurologic phenotype with anatomical abnormalities similar to those seen in biopsy materials.
The enzyme 3-hydroxyanthranilate 3,4-dioxygenase reacts with its substrate and oxygen to synthesize a product that immediately rearranges to quinolinic acid. Quinolinic acid, a metabolite of tryptophan, is an endogenous excitotoxin and an agonist of NMDA receptors. It kills neurons through the activation of NMDA receptors. The activity of this enzyme increases in the brains of HD patients, especially in the striatum (Schwarcz, Schwarcz, Okuno, White, Bird, & Whetsell, 1988).
Glutamate receptor mediated cytotoxicity, contributes to cell death in HD (Hannson, 1999). Mice transgenic for trinucleotide repeats of exon 1 of the HD gene are protected from acute striatal excitotoxic lesions. Infusion of quinolinic acid into the striatum results in massive cell death in wild type mice, but transgenic mice suffer no damage, but a 17% the volume of the striatum reduces by 17%. The mutant HD gene induces profound change in untreated mice and makes them resistant to excessive NMDA receptor activation
Initial neuronal cytoplasmic toxicity leads to huntingtin
cleavage, nuclear translocation of fragments, and selective neurodegeneration
(Hodgson et al., 1999). Mice that express mutant huntingtin
suffer electophysiologic abnormalities because of cytoplasmic dysfunction.
At 12 months medium spiny neurons of the lateral striatum were degenerating.
This was due to translocation of N-terminal huntingtin fragment to the
nucleus, this occurred whether or not aggregates formed (Hodgson et
At the present time, no treatments suppress, reverse, or prevent HD. The first steps in treatment are education and the creation of therapies that accommodate each patient’s specific needs. Depression, which occurs early in the disease, is treated with tricyclic antidepressants (TCAs) and selective serotonin reuptake inhibitors. A positive side effect of TCAs is the prevention of insomnia and weight gain. (Some HD patients have trouble sleeping and maintaining an appetite.) Agitation is controlled with anxiolytics. Both dopamine blocking and monoamine depleting drugs, types of neuroleptics, suppress choreic movement (Dept.of Neurology at Baylor College of Medicine, 2000).
Clinical diagnosis of HD includes neuroimaging studies, genetic testing, and examination of family history. Computed tomography (CT) scans and magnetic resonance imaging (MRI) identify a characteristic atrophy of the caudate nucleus (Figure 6). These imaging studies are used to support clinical findings. Their main role, however, is to determine whether or not other conditions are causing the clinical symptoms (Harper, 1996).
Figure 6: Magnetic resonance imaging of a patient
with Huntingdon's disease.
A decrease in the uptake and metabolism of glucose precedes tissue loss in the caudate putamen. Positron-emission tomography generates images of cerebral blood flow, brain metabolism, and other chemical processes. Radioisotopes are injected and their emissions are measured by a gamma-ray detector system. For example, 18F-labeled deoxyglucose is used to measure glucose metabolism. Mazziota measured cerebral glucose metabolism and found that 30% of at risk individuals have metabolic abnormalities in the caudate nucleus (1987) (Figure 7).
(Taken with permission from The Whole Brain Atlas; click on the picture to be linked.)
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