When more is less: Pathogenesis of glutamine repeat neurodegenerative diseases
چکیده
Five neurodegenerative diseases are caused by expanding CAG triplet repeats coding for polyglutamine. They all involve loss of selected populations of neurons, usually in adulthood. How the genetic lesions cause progressive neuronal degeneration is unknown. Unraveling the pathogenesis of these disorders will help elucidate pathways of neuronal cell death. Triplet repeat disorders involve the recently identified phenomenon of unstable DNA, in which repeating units of 3 nucleotides such as CAG expand during vertical transmission and cause disease (La Spada et al., 1994). They can be divided into two types. The first type (Figure 1) involves expanding CAG repeats coding for polygluta-mine. The normal length of the repeat is from 6 or 7 to about 30, and the disease is present when the repeat expands to 35-40 or more. Except for the androgen receptor of spinal and bulbar muscular atrophy (SBMA), none of the caus-ative genes has a known function or substantial homology with any known gene in the database. In the second type of disease (Table 1), triplet repeats such as CTG or CCG are present in mRNA outside the open reading frame (La Spada et al., 1994; Ross et al., 1993). In all of the glutamine repeat diseases, there is loss of neurons with gliosis, but without deposition of extracellular material or intracellular inclusion bodies. Though the expression patterns of the causative genes are widespread, the disorders involve loss of neurons within specific regions of the brain and spinal cord (Figure 1). It is possible that the glutamine repeat diseases share similar mechanisms of pathogenesis. Glutamine Repeat Diseases and Causative Genes Huntington's disease (HD) is the most common glutamine repeat disease. It is an autosomal dominant neurodegen-erative disorder characterized by abnormal movements including chorea, dementia, and emotional disorders. The pathology is notable for selective neuronal vulnerability of medium spiny projection neurons in the caudate and putamen. After a long search, the HD gene was identified and found to have an expanding CAG repeat (Huntington's Disease Collaborative Research Group, 1993). The mRNA contains a long open reading frame coding for a predicted protein of 348 kDa. Immediately adjacent to the glutamine repeat, there are two proline repeats interrupted by a pro-line-rich region. The protein product of the HD gene (hun-tingtin), like the mRNA, has a widespread expression in both the brain and the periphery (Sharp et al., 1995; Trot-tier et al., 1995). Within the brain, it is predominantly neu-ronal with …