Figure 5.

Deletion of one Nlk allele rescues SCA1 cerebellar phenotypes in mice. A, In the dowel rod walking test, Atxn1^154Q/+ mice showed increased latency to reach the sides of the dowel compared with WT and Nlk^+/− littermates (left). They also walked off fewer times in the 120 s interval (right). In contrast, Atxn1^154Q/+; Nlk^+/− mice exhibited marked reduction in the time for the first side touch and increased the number of side touches compared with Atxn1^154Q/+ littermates. Genotypes are color-coded as indicated. Error bars indicate SEM. B–D, Cerebellar neuropathology is partially rescued in Purkinje cells of Atxn1^154Q/+ mice lacking one allele of Nlk. B, Representative confocal images showing Purkinje cell morphology stained with anti-calbindin antibody from age-matched littermates. C, Quantitative analysis of calbindin immunofluorescence is an indirect measure of cerebellar Purkinje cell soma and dendritic integrity. Mean fluorescence intensity of optical rectangular subsections from the same folia of 38- to 39-week-old animals was plotted as the distance from the perikaryon center. Nlk heterozygosity partially rescues the Atxn1^154Q/+ loss of dendritic arborization phenotype. Error bars indicate SEM. D, Quantification of the cerebellar molecular layer thickness at the primary fissure from 38- to 39-week-old mice (shown by arrow in B). Atxn1^154Q/+ mice (four sections per animal; n = 3) significantly decreased molecular layer thickness compared with WT littermates. *p = 0.015 (ANOVA). Loss of one Nlk allele (four sections per animal; n = 2) rescued defects of the molecular layer thickness in Atxn1^154Q/+ mice. *p = 0.004 (ANOVA). Error bars indicate SEM.