44: Genetic Mechanisms in Degenerative Diseases of the Nervous System

Introduction

• Expanded Trinucleotide Repeats Characterize Several Neurodegenerative Diseases

  • Huntington Disease Involves Degeneration of the Striatum

  • Spinobulbar Muscular Atrophy Is Due to Abnormal Function of the Androgen Receptor

  • Hereditary Spinocerebellar Ataxias Include Several Diseases with Similar Symptoms but Distinct Etiologies

• Parkinson Disease Is a Common Degenerative Disorder of the Elderly

• Selective Neuronal Loss Occurs After Damage to Ubiquitously Expressed Genes

• Animal Models Are Powerful Tools for Studying Neurodegenerative Diseases

  • Mouse Models Reproduce Many Features of Neurodegenerative Diseases

  • Invertebrate Models Manifest Progressive Neurodegeneration

• Several Pathways Underlie the Pathogenesis of Neurodegenerative Diseases

  • Protein Misfolding and Degradation Contribute to Parkinson Disease

  • Protein Misfolding Triggers Pathological Alterations in Gene Expression

  • Mitochondrial Dysfunction Exacerbates Neurodegenerative Disease

  • Apoptosis and Caspase Modify the Severity of Neurodegeneration

• Advances in Understanding the Molecular Basis of Neurodegenerative Diseases Are Opening Possibilities for Approaches to Therapeutic Intervention

• An Overall View

The major degenerative diseases of the nervous system—Alzheimer, Parkinson, and the triplet-repeat diseases (Huntington and the spinocerebellar ataxias)—afflict nearly 5 million people in the United States alone, and more than 25 million people throughout the world. Although this is a relatively small percentage of the population, these diseases bring a disproportionate amount of suffering and economic loss, not only to their victims but also to the families and friends of the afflicted.

Most of these disorders strike in mid-life or later; aging itself may in fact contribute to susceptibility. With the exception of Alzheimer disease, the first symptoms to appear usually involve loss of control of fine motor movements, although Huntington disease can first manifest itself in cognitive deficits. Nevertheless, the end result is the same. After a lengthy period of progressive deterioration, usually 10 to 20 years, the affected individual dies a terrible, helpless death.

The late-onset neurodegenerative diseases can be grouped conceptually into two categories: sporadic (unknown etiology) and inherited. Alzheimer disease and Parkinson disease are predominantly sporadic; inherited forms afflict a small number of patients. The triplet-repeat diseases, however, are notable for their dominant pattern of inheritance and the dynamic nature of the pathological mutation, an elongation of a CAG repeat tract that is subject to further expansion. Among the triplet-repeat neurodegenerative diseases are Huntington disease, the spinocerebellar ataxias, dentatorubropallidoluysian atrophy, and spinobulbar muscular atrophy. Identification of the molecular basis of some of these disorders has facilitated diagnosis and classification and provides hope for eventual treatment.

Expanded Trinucleotide Repeats Characterize Several Neurodegenerative Diseases

Huntington Disease Involves Degeneration of the Striatum

Huntington disease usually strikes in early or middle adulthood and affects 5 to 10 people per 100,000. The clinical presentation includes loss of motor control, cognitive impairment, and affective disturbance. Motor-control problems most commonly manifest themselves early as chorea, involuntary jerky movement that involves the small joints at first but then gradually creates instability of gait as the trunk and legs are affected. Fast, fluid movements are replaced by rigidity and ...