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Neurological disorders represent a large share of the disease burden worldwide, and the incidence of age-related forms will continue to rise with life expectancy. Gene targeting has been and will remain a valuable approach to the generation of clinically relevant mouse models from which to elucidate the underlying molecular basis. However, as the aetiology of the majority of these conditions is still unknown, a reverse approach based on large-scale random chemical mutagenesis is now being used in an attempt to identify new genes and associated signalling pathways that control neuronal cell death and survival. Here, we review the characterisation of a novel model of autosomal dominant cerebellar ataxia which shows general growth retardation and develops adult-onset region-specific Purkinje cell loss as well as cataracts and defects in early T-cell maturation. We have previously established that the mutated protein Af4, which is a member of the AF4/LAF4/FMR2 (ALF) family of transcription cofactors frequently translocated in childhood leukaemia, undergoes slower proteasomal turnover through the ubiquitin pathway and abnormally accumulates in Purkinje cells of the cerebellum. We have also shown that Af4 functions as part of a large multiprotein complex that stimulates RNA polymerase II elongation and mediates chromatin remodelling during transcription. With the forthcoming identification of the gene targets that trigger Purkinje cell death in the robotic cerebellum, and the functional conservation among the ALF proteins, the robotic mouse promises to deliver important insights into the pathogenesis of human ataxia, but also of mental retardation to which FMR2 and LAF4 have been linked.

Original publication




Journal article



Publication Date





175 - 183


Age Factors, Animals, Cerebellar Ataxia, Chromatin Assembly and Disassembly, DNA-Binding Proteins, Disease Models, Animal, Humans, Mice, Mice, Mutant Strains, Mutagenesis, Nuclear Proteins, Phenotype, Purkinje Cells