The up-regulation of Superoxide Dismutase-1 (SOD1) influences neurodegeneration in a Drosophila model of Machado-Joseph disease (MJD)

Polyglutamine (polyQ) diseases are dominantly inherited, late onset, neurodegenerative ers. Neurodegeneration is caused by expansion of CAG repeats in the coding region of th disord e gene and expression of polyQ-expanded proteins (1,3,4,6,7, 20, 21, 25). This expanded CAG repeat results in a genetic “gain-of-function” mechanism that allows the expanded protein to cause disease by an unknown mechanism (1). Currently there are nine known polyQ diseases that are caused by polyQ expanded proteins. They are Huntington disease (HD), spinal bulbar muscular atrophy, dentatorubro pallidoluysian atrophy, and six dominantly inherited spinocerebellar ataxias (SCA 1, 2, 3, 6, 7, and 17) (2,3). Interestingly, outside of the polyQ expansion the affected proteins of these diseases show no homology to each other, and even still some of the normal functions of these proteins are not known (1). All of the polyQ diseases are linked by the expanded CAG repeat in the coding portion of the gene. The CAG repeats are highly unstable and dynamic in nature, and the number of repeats and disease severity can also vary a great deal. It is known that in all polyQ diseases, the larger the CAG expansion, the earlier the onset of the disease phenotype, and typically the more severe the course of the disease (4, 5). It is not known how these diseases cause neurodegeneration, however, in many polyQ diseases, abnormal protein aggregation, often seen as nuclear inclusions (NI), can be found accompanying the disease phenotype (6). Table 1: Adapted from Paulson et al., 2000. This table shows how the polyQ expansions in very different proteins can cause similar disease phenotypes such as protein aggregation, often seen as nuclear inclusions (NI) adapted from Paulson et al., 2000 (18) shows the way in which different polyQ diseases have similar features such as NIs as well as highly unstable glutamine repeats in the coding portion of the affected gene. Formation of NIs was thought to be related to pathogenesis of the polyQ diseases, but more recent evidence suggests that they result from end-stage protective cellular mechanisms. NIs may be thought of as the cell’s last resort to try and ameliorate disease progression (5). Another interesting facet of polyglutamine diseases is that they act in a region specific manner in the brain. All polyQ proteins are expressed throughout the brain, but only degenerate certain particular parts of the brain. This indicates that although polyQ diseases act in similar ways, there are definite and obvious differences between them. This presumably is a result of the way that these different proteins interact in different and specific pathways in brain cells