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Mystery surrounding the events leading to degeneration of neurones in hereditary ataxias has deepened, as an immunohistochemical study discloses complete absence of nuclear inclusions in Purkinje cells in human brain stems. At least two opposing explanations are possible.
Nuclear inclusions are of interest because they are usually common in Purkinje cells in the brain stem in 10 or so inherited neurodegenerative diseases and contain products of the CAG repeat sequences in the disease gene. The authors chose four diseases with different degrees of cerebellar degeneration and compared the extent of nuclear inclusions, for evidence of a common pathogenesis.
The results were perplexing. Nuclear inclusions positive for either of two gene products—ubiquitin or polyglutamine—were restricted to the dentate nucleus in three diseases—spinocerebellar ataxia (SCA) 1, SCA3, and dentatorubral pallidoluysian atrophy (DRPLA)—and Golgi cells in SCA1, SCA2, and DRPLA. None occurred in Purkinje cells from any source.
A link between nuclear inclusions and neurodegeneration consistent with the results could be explained in two ways. If they were lethal early cell death could lead to their absence or if they were protective their absence would indicate impending cell death. Others have observed lack of nuclear inclusions in other diseases in this group. It seems that only more effort will unravel any link.
Brain stems were obtained from 13 patients with SC1, SC2, SC3, or DRPLA and three controls with neither neurological nor psychiatric conditions Serial sections from each were stained for ubiquitin or polyglutamine with specific antisera.