Characterization of TBP/TBP-1 and CHIP/CHN-1 impact on neuron function

Spinocerebellar ataxia type 17 (SCA17) and type 48 (SCA48) are both characterized by cerebellar-cognitive-behavioral features and incomplete penetrance. SCA17 is caused by a CAG/CAA (polyQ) repeat expansion in the TBP gene, which encodes the general transcriptional factor TATA-box binding protein, whereas SCA48 is associated with heterozygous variants in the STUB1 gene, which encodes CHIP, an E3 ubiquitin ligase with co-chaperone activity. We have recently demonstrated a digenic inheritance of the TBP/STUB1 genotype, which explains the incomplete penetrance of these diseases. Specifically, SCA17 is monogenic for TBP expansions with >47 polyQ and digenic TBP/STUB1 for intermediate alleles (41-46 polyQ). To unravel the nature of TBP-CHIP interaction, we took advantage of the nematode Caenorhabditis elegans whose genome harbors orthologs for both TBP and STUB1, named tbp-1 and chn-1, respectively. We have generated SCA17 animal models by overexpression in all neurons of the cDNA of human TBP alleles with 38 (wild-type, TBPWT), 43 (intermediate, TBPQ43), and 54 repeats (fully-penetrant, TBPQ54). TBPQ54 animals showed strong defects in responses to gentle and nose touches, but no defects in harsh touch, backward movement, or thrashing. In contrast, chn-1(by155) knockout caused defects in backward movement, but not in gentle or nose touch responses. These preliminary findings suggest that the two genes may influence different neuronal types. Specifically, the fully-penetrant expansion mutation in TBP possibly affects mechanosensory neurons, whereas chn-1 knockout impacts GABAergic motoneurons function. The generation of digenic SCA17 animal models will elucidate the possible genetic interaction of the two genes and in which class of neurons this interaction is exerted.