Figure 6. Loss of wild-type Atxn1 function worsens SCA1 neuropathology in mice.

(a,b) Atxn1 154Q/− animals showed a worsened rotarod performance (*P<0.05, **P<0.005) and earlier lethality (P<1×10⁻⁶) than Atxn1 154Q/+ mice.

(c) Model for SCA1 neuropathology. In wild-type individuals, there are at least two distinct and mutually exclusive ATXN1-associated endogenous protein complexes in vivo. The formation of one of these complexes (ATXN1/RBM17) appears to be regulated in that it requires phosphorylation of ATXN1. Polyglutamine expansion in ATXN1 favors formation of the RBM17-containing complex, thereby enhancing one endogenous function and contributing to neuropathology via a gain-of-function mechanism. Polyglutamine expansion concomitantly decreases the formation of CIC-containing complex, resulting in a partial loss of function.