Emerging pathogenic pathways in the spinocerebellar ataxias

Abstract

The spinocerebellar ataxias (SCAs) are diseases characterized by neurodegeneration of the spinocerebellum. To date, 28 autosomal dominant SCAs have been described and seventeen causative genes identified. These genes play a role in a broad range of cellular processes. Recent studies focused on the wild type and pathogenic functions of these genes implicate both gene expression and glutamate-dependent and calcium-dependent neuronal signaling as important pathways leading to cerebellar dysfunction. Understanding how these genes cause disease will allow a deeper understanding of the cerebellum in particular as well as neurodegenerative disease in general.

Figure 1

Gene expression and dendritic signaling pathways affected in SCA pathogenesis. A general neuron is shown because Purkinje cell involvement in SCA3 pathogenesis is minimal; however, the synaptic events specifically associated with Purkinje cell signaling are depicted. Note that the FGF14/SCN8A interaction takes place in the proximal dendrite and cell body. SCA proteins are represented in red while the proteins they interact with based on experimental data are depicted in light blue. Hypothetical proteins in the complex are shown in dark blue. Standard HUGO gene names are used except for TFIIB (GTF2B), NCoR (NCOR1/NCOR2), RORα (RORA), Tip60 (KAT5), AMPA (AMPA-type glutamate receptor), SERCA (sarco/endoplasmic reticulum calcium-ATPase). In addition to key protein interactions, the genes downregulated in a SCA1 transgenic mouse model are also noted in the dendrite. ATXN1, 2, 3, and 7 are the proteins involved in SCA1, 2, 3, and 7 respectively (also see Table 1).