CHAPTER NINE
DEGENERATIVE DISEASES

HUNTINGTON'S DISEASE

Huntington's Disease (HD) is a fatal autosomal dominant condition that begins usually in the

HD: Atrophy of the caudate and hydrocephalus ex vacuo	GFAP immunostain, showing gliosis. Left: HD; right: normal caudate nucleus

fourth decade of life and is characterized by behavioral changes, chorea, and dementia. Gross examination of the brain reveals atrophy of the caudate nucleus and putamen and dilatation of the anterior horns of the lateral ventricles, which can be detected by neuroimaging. Cortical atrophy is also present in advanced cases.

Microscopically, there is loss of medium size spiny internuncial neurons in the caudate nucleus and putamen, loss of cortical neurons, and gliosis. Proliferation of reactive astrocytes causes the affected nuclei to appear more cellular than normal.

The molecular abnormality of HD is CAG trinucleotide expansion of the huntingtin gene on chromosome 4p. This adds a polyglutamine segment to the huntingtin protein. This protein is widely expressed throughout the brain. It is thought that the CAG-expanded huntingtin has a toxic function. However, huntingtin is a key cellular protein involved in cellular transport and is important for cell viability. Therefore, loss of huntingtin function may also contribute to the pathogenesis of HD. The CAG triplet expansion is probably due to malfunction of cellular processes that repair strand breaks and remove mispaired bases from DNA. The expanded huntingtin, conjugated with ubiquitin, forms aggregates (inclusions) in the nuclei of affected neurons. These inclusions can be detected by immunohistochemistry using antibodies to huntingtin. These findings suggest that there is an error in the proteolytic degradation of the expanded huntingtin. Normally, this degradation takes place in cellular chambers called proteasomes and involves conjugation of huntingtin with ubiquitin. Impairment of this process apparently causes huntingtin-ubiquitin complexes to be translocated into the nuclei.

THE UBIQITIN-PROTEASOME  AND LYSOSOMAL SYSTEM IN NEURODEGENERATIVE DISEASE Protein recycling in cells is done by 2 systems, the ubiquitin-proteasome system (UPS) and the lysosomal system. The UPS consists of the proteasome, a barrel-shaped multi-enzyme complex, and  ubiquitin, a small protein that tags proteins targeted for proteasomal degradation. The UPS degrades abnormal and damaged proteins and regulates also the turnover of normal short-lived proteins that are important for regulation of cell function. Abnormal forms of proteins, including tau, huntingtin, and mutant synuclein, form aggregates that cannot be digested in proteasomes and accumulate in the cytoplasm or nucleus in the form of inclusions. Such aggregates damage the UPS. Proteolysis in the UPS plays an important physiological role in growth and remodeling of axons, dendrites, and synapses. Impairment of the UPS is seen in several neurodegenerative diseases, including AD, Parkinson's disease, Huntington's disease, other CAG trinucleotide repeat disorders, and ALS. Lysosomes degrade long-lived proteins, chunks of cytoplasm, and entire organelles. These functions protect cells from accumulation of damaged organelles that could induce apoptosis, remove metabolic waste, and help cells survive and adapt to changes in their environment. Abnormally folded proteins that occur in neurodegenerative diseases are processed through lysosomes. Accumulation of such products and of lipofuscin, impairs lysosomal function. Proteolytic activity (and the ability for cell renewal) decline with advancing age. This is probably responsible for the clinical onset of neurodegenerative diseases in old people.

CAG repeats on other genes are also seen in spinobulbar muscular atrophy (Kennedy's disease), Machado-Joseph disease, an autosomal dominant ataxia seen mainly in Portugese of Azorean descent, and cerebellar degenerations. Paternally inherited HD shows the phenomenon of anticipation, i.e. the number of repeats increases in the offspring, resulting in earlier onset and more severe disease. Biochemical analysis of the striatum in HD shows loss of neurotransmitters, including GABA, acetylcholine and glutamate, which correlates with the loss of small neurons. Decrease of GABA and unbalanced dopamine activity result in chorea.

A rare form of chorea, beginning in adolescence or early adult life, is associated with an erythrocyte abnormality (chorea with acanthocytosis). Pathologically, this entity is similar to Huntington's disease but is caused by a different gene defect. Sydenham Chorea is a transient disorder in rheumatic fever caused by antibodies that react with neuronal antigens in the basal ganglia.

Further reading

Martinez-Vicente M, Sovak G, Cuervo AM. Protein degradation and aging. Exp Gerontol. 2005;40:622-33. PubMed

Updated: January, 2008