The pathogenesis of spinocerebellar ataxia

Six forms of spinocerebellar ataxia (SCA) are caused by pathological cytosine-adenine-guanine (CAG) trinucleotide repeat expansions in the coding region of the mutated genes. The translated proteins contain abnormally long polyglutamine stretches, and SCA-1, SCA-2, SCA-3/Machado-Joseph disease (MJD), SCA-6, SCA-7, and SCA-17 are "polyglutamine diseases". Despite their clinical and genetic heterogeneity, the ataxia-causing lesions in the brain invariably affect the "cerebellar module" that is defined as a reciprocal circuitry between the cerebellar cortex, the dentate nuclei, and the inferior olivary nuclei. While the neurons of the basis pontis do not properly belong to this module, pontine atrophy is an important additional lesion in SCA-1, SCA-2, and SCA-7. The descriptive term olivopontocerebellar atrophy (OPCA) applies to these forms whereas SCA-6 is the prototype of "pure" cerebellar cortical or cerebello-olivary atrophy. Purkinje cells have an elaborate dendritic tree, and atrophy of these most remarkable cells has captured the attention of many morphologists. Almost invariably, the loss of Purkinje cells entails retrograde neuronal degeneration in the inferior olivary nuclei. However, SCA-6 is an exception, and many olivary neurons survive. Similarly, stellate, basket, and granule cells do not undergo commensurate retrograde atrophy when Purkinje cells disappear. The dentate nucleus displays "grumose" degeneration in SCA-3/MJD while the cerebellar cortex and the inferior olivary nuclei remain largely unaffected. The role of polyglutamine-containing intranuclear and cytoplasmic inclusion bodies in SCA remains unknown but protein aggregation may be the common step in the pathogenesis of these otherwise rather heterogeneous disorders.