Nuclear Inclusions in Glutamine Repeat Disorders: Are They Pernicious, Coincidental, or Beneficial?

• Published in: Cell Vol. 95; no. 1; pp. 1 - 4
• Main Author: Sisodia, Sangram S
• Format: Book Review Journal Article
• Language: English
• Published: United States Elsevier Inc 02.10.1998
• Subjects: Animals; Cell Nucleus; Humans; Inclusion Bodies; Neurodegenerative Diseases - etiology; Neurodegenerative Diseases - genetics; Peptides - physiology; Repetitive Sequences, Amino Acid
• ISSN: 0092-8674; 1097-4172
• DOI: 10.1016/S0092-8674(00)81743-2

Expansions of CAG triplets within the coding regions of target genes are the cause of a variety of autosomal dominant neurodegenerative disorders, including Huntington's disease (HD), several spinocerebellar ataxias (SCAs), dentatorubralpallidoluysian atrophy (DRPLA), and X-linked spinocerebellar muscular atrophy (SBMA) (reviewed in Paulson and Fishbeck, 1997). HD and DRPLA are manifested by unusual movements and dementia, and SCA1 and SCA3 (commonly termed Machado-Joseph disease) are characterized by ataxia and incoordination. These disorders are characterized by an unusual patterns of paternal inheritance, termed genetic "anticipation." In successive generations of a pedigree, the severity of disease increases and age-of-onset of clinical symptoms decreases. Remarkably, the age-of-onset is inversely correlated with the length of the "abnormal" CAG expansion. Although the target genes have little homology, except in the highly polymorphic CAG tract, pathogenicity is invariably provoked when the disease chromosome expands to a "threshold" of between 35-40 CAG repeats. Curiously, despite the widespread expression of each polypeptide, each disorder is characterized by a highly stereotypical pattern of degeneration of selected subpopulations of neurons. For example, the chorea and dementia in HD are related to the degeneration of subsets of striatal and cortical neurons. In SCA1, SCA3, and DRPLA, a variety of cell populations undergo degeneration, particularly in the cerebellum, while in SBMA spinal and brainstem motor neurons are most vulnerable.