Disease Mechanisms in Different Forms of Cerebellar Ataxia

Progressive cerebellar ataxia forms one of the major movement disorders. Over the past decades we have uncovered that in most forms of progressive cerebellar ataxias the Purkinje cells start to degenerate in the so-called zebrin-negative zones. For example, in mid-aged mouse models of SCA1, SCA6 and Niemann-Pick type C one can distinguish clearly survival of zebrin-positive zones amidst the remnant neuropil of disappearing zebrin-negative Purkinje cells. In other forms of progressive cerebellar ataxia, like A-T and ERCC1-disease, one can also observe that the most prominent degeneration starts in the area where zebrin-negative Purkinje cells dominate, i.e., the anterior lobe, but here the differences among the zones are more gradual. The overall differences among zebrin-negative and zebrin-positive areas may be due to the fact that Purkinje cells in zebrin-negative zones have a tendency to fire with relatively high simple spike firing frequencies, whereas the zebrin-positive ones fire at relatively low firing frequencies, protecting them from early cytotoxicity. In my lecture I will elaborate upon the specific disease mechanisms that may further explain the fine-graded differences among the various forms of cerebellar ataxia.