Huntington disease

Definition: Huntington disease is a neurodegenerative disorder that is inherited as an autosomal dominant trait. Huntington disease is characterized by the progressive loss of cognitive function, dementia and motor defects as a consequence of neuronal dysfunction and loss.

Huntington disease (HD) is an inherited autosomal-dominant disease characterized clinically by progressive movement disorders and dementia and histologically by degeneration of striatal neurons.

The movement disorder chorea consists of jerky, hyperkinetic, sometimes dystonic movements affecting all parts of the body; patients may later develop parkinsonism with bradykinesia and rigidity. The disease is relentlessly progressive, with an average course of about 15 years to death.

Huntington disease (HD) is caused by the expansion of a CAG repeat within the coding region of a novel gene on 4p16.3 coding for huntingtin (MIM.143100).

An increase in the length of a CAG triplet repeat (polyglutamine tract) in the huntingtin gene (HD) underlies the pathogenesis of the disease, although the function of the wild-type or the ’extended’ proteins remains elusive.

Clinical synopsis

The age at onset is most commonly in the fourth and fifth decades and is related to the length of the CAG repeat in the HD gene. Motor symptoms often precede the cognitive impairment.

The movement disorder of HD is choreiform, with increased and involuntary jerky movements of all parts of the body; writhing movements of the extremities are typical. Early symptoms of higher cortical dysfunction include forgetfulness and thought and affective disorders, but there is progression to a severe dementia.

HD patients have an increased risk of suicide, with intercurrent infection being the most common natural cause of death. Given the ability to screen for disease-causing mutations and the devastating nature of the disease, HD is often the focal point of discussion of ethical issues in genetic diagnosis.

Morphology

HD affects specific areas of the brain; mostly in the striatum, which is composed of the caudate nucleus and putamen, but other areas greatly affected include the substantia nigra, layers 3, 5 and 6 of the cerebral cortex, hippocampus, angular gyrus, purkinje cells in the cerebellum, lateral tuberal nuclei of the hypothalamus and parts of the thalamus.

These area are affected according to their structure and the types of neurons they contain, reducing in size as they lose cells.

Striatal spiny neurons are the most vulnerable, particularly ones with projections towards the external globus pallidus, those projecting to the internal pallidum and interneurons are less affected. HD also causes astrogliosis.

This pathological mechanism is in accordance with the knowledge of the striatum’s functions and is able to explain the early appearance of chorea. It has been proposed that the striatum’s subthalamic nuclei send control signals to the globus pallidus, which initiates and modulates motion. The weaker signals from subthalamic nuclei due to the disease thus hinder initiation and modulation of movement, resulting in chorea.

On macroscopic examination, the brain is small and shows striking atrophy of the caudate nucleus and, less dramatically, the putamen. The globus pallidus may be atrophied secondarily, and the lateral and third ventricles are dilated. Atrophy is frequently also seen in the frontal lobe, less often in the parietal lobe, and occasionally in the entire cortex.

On microscopic examination, there is severe loss of striatal neurons; the most dramatic changes are found in the caudate nucleus, especially in the tail and portions nearer the ventricle.

The putamen is less involved. Pathologic abnormalities develop in a medial-to-lateral direction in the caudate and from dorsal to ventral in the putamen.

The nucleus accumbens is the best preserved structure. Both the large and small neurons are affected, but loss of the small neurons generally precedes that of the large. The medium-sized, spiny neurons that use GABA as their neurotransmitter, along with enkephalin, dynorphin, and substance P, are especially affected.

Two populations of neurons are relatively spared in the disease: the diaphorase-positive neurons that contain nitric oxide synthase and the large cholinesterase-positive neurons; both appear to serve as local interneurons.

There is also fibrillary gliosis that is more extensive than in the usual reaction to neuronal loss. There is a direct relationship between the degree of degeneration in the striatum and the severity of clinical symptoms.

Loci modifying the age of onset (12900792)

 4p16
 6p21-23
 6q24-26

Pathogenesis

Huntington disease is caused by polyglutamine expansion in huntingtin, a 350kD protein that is ubiquitously expressed and widely distributed at the subcellular level.

Huntington disease (MIM.143100) may be due to a toxic gain-of-function caused by abnormal protein-protein interactions related to the elongated polyglutamine sequence of huntingtin. Thus, the binding of distinct proteins to the polyglutamine region could either confer a new property on huntingtin or alter its normal interactions with other proteins.

Increasing evidence indicates that the neuronal defect that is observed in Huntington disease is a consequence of defects in microtubule-dependent vesicular transport.

Huntingtin is found in the nucleus and the cytoplasm associated with vesicles and microtubules. Interestingly, huntingtin interacts with huntingtin-associated protein (HAP1), a protein that binds to the p150Glued subunit of dynactin and the pericentriolar material 1 protein (PCM1), which is involved in both centrosome and basal-body function.

HAP1 is transported along axons, where it might function in linking transported vesicles with the cytoskeleton and molecular motors such as dynein.

Huntingtin controls the microtubule-assisted vesicle transport of the brain-derived neurotrophic factor (BDNF).

BDNF is produced in the cortex but is released in the striatum, where it promotes cell survival; therefore, defective vesicle transport might contribute to the pathogenesis of Huntington disease.

The identification of the huntingtin-interacting protein (HIP1) - a peptide that shares similarity to the budding yeast Sla2p, which is involved in cytoskeleton function - provides further supporting evidence for the role of huntingtin in the organization of the cytoskeleton and microtubule-based transport.

HIP1 interacts with huntingtin-interacting protein interactor (HIPPI), which is homologous to the C. reinhardtii intraflagellar transport IFT.

In addition, studies in fibroblast cultures that are derived from mice and patients with Huntington disease exhibit aberrant centrosome numbers, reduced mitotic index, high frequency of aneuploidy and persistence of the MIDBODY103.

Interestingly, the interaction between huntingtin and HIP1 is inversely correlated with the length of the polyglutamine tract, which provides a clue to the mechanism of this devastating disease and indicates once again that the regulatory properties of the centrosome for microtubule-based transport are relevant to disease onset and progression.

 Amyloid deposition, huntingtin and Huntington disease

Huntington disease results from the aggregation of the neuronal protein huntingtin. Compared with the other conformational dementias, the appearance of intracellular inclusions is a late feature of the disease. The reason for this is that the initial aggregates are efficiently removed by cellular chaperones and it is only when these become overwhelmed, after many years, that the aggregates develop and with them the clinical manifestations.

The cause of the aggregation is the presence in the tail of the huntingtin molecule of a large glutamine-repeat domain that can undergo an inheritable extension. If the size of this domain extends beyond 37 repeats, then intermolecular bonding between tails forms the aggregates.

An intriguing explanation for the beta-linked structure of the huntingtin aggregates, which has wider implications for amyloids in general, has recently been proposed.

This model suggests that the glutamine repeats form a cylindrical sheet made up of beta-strands with 20 residues per helical turn, and provides a satisfying hypothesis for the crucial threshold of 37-40 glutamine repeats that are required for neurodegeneration in Huntington disease.

A single turn with 20 residues would be unstable, as there is nothing to hold it in place; however, 2 turns with 40 residues are stabilized by the hydrogen bonds between their amides, and such initial 2-turn structures can then act as nuclei for further helical growth.

 Amyloid and huntingtin

Huntington disease results from the aggregation of the neuronal protein huntingtin.

Compared with the other conformational dementias, the appearance of intracellular inclusions is a late feature of the disease. The reason for this is that the initial aggregates are efficiently removed by cellular chaperones and it is only when these become overwhelmed, after many years, that the aggregates develop and with them the clinical manifestations.

The cause of the aggregation is the presence in the tail of the huntingtin molecule of a large glutamine-repeat domain that can undergo an inheritable extension. If the size of this domain extends beyond 37 repeats, then intermolecular bonding between tails forms the aggregates.

An intriguing explanation for the -linked structure of the huntingtin aggregates, which has wider implications for amyloids in general, has recently been proposed.

This model suggests that the glutamine repeats form a cylindrical sheet made up of beta-strands with 20 residues per helical turn, and provides a satisfying hypothesis for the crucial threshold of 37–40 glutamine repeats that are required for neurodegeneration in Huntington disease.

A single turn with 20 residues would be unstable, as there is nothing to hold it in place; however, 2 turns with 40 residues are stabilized by the hydrogen bonds between their amides, and such initial 2-turn structures can then act as nuclei for further helical growth.

Pathogenesis

The functional significance of the loss of medium spiny striatal neurons is to dysregulate the basal ganglia circuitry that modulates motor output. The loss of the striatal inhibitory output to the external portion of the globus pallidus results in increased inhibitory input to the subthalamic nucleus. This inhibition of the subthalamic nucleus prevents it from exerting its regulatory effects on motor activity and thus leads to choreoathetosis. The structural basis of the cognitive changes associated with the disease remains unclear, although there is evidence of neuronal loss from cerebral cortex as well.

The HD gene, located on 4p16.3, encodes a predicted protein, called huntingtin, of 348-kD molecular mass.210 The coding region of the gene contains a polymorphic CAG trinucleotide repeat encoding a polyglutamine region of the protein. Normal HD genes contain 6 to 35 copies of the repeat; in disease-causing genes, the number of repeats is increased. The disease is thus an example of the "trinucleotide repeat disorders". There is strong genotype-phenotype correlation, in the sense that the larger the number of repeats, the earlier the onset of the disease, although other genetic modifiers play a role.

Repeat expansions occur during spermatogenesis, and paternal transmission is associated with early onset in the next generation.

Newly occurring mutations are uncommon, and most apparently sporadic cases can be related to errors in paternal identification or the death of a parent before expression of the disease. Some unaffected fathers have expanded repeats that are further expanded during transmission to their children.

The biologic function of huntingtin and how mutations cause disease remain unknown but are the focus of much study. The protein is clearly essential, as targeted gene disruption in the mouse has demonstrated an early embryonic lethal phenotype. In tissue from HD patients, both wild-type and mutant protein are present. The expanded polyglutamine repeat results in protein aggregation and formation of intranuclear inclusions.

There are potential interactions between aggregated huntingtin and pathways involved in protein turnover, oxidative injury, and glutamate toxicity. Additionally, huntingtin with expanded polyglutamine repeats may alter transcription.

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