Heat shock proteins (HSPs) play an important role in cell homeostasis and protect against cell damage. They were previously identified as key players in different ataxia models. HSF1 is the main transcription factor for HSP activation. HSF1-deficient mice (HSF1-/-) are known to have deficiencies in motor control test. However, little is known about effects of HSF1-deficiency on locomotor, especially gait, coordination. Therefore, we compared HSF-deficient (HSF1-/-) mice and wildtype littermates using an automated gait analysis system for objective assessment of gait coordination. We found significant changes in gait parameters of HSF1-/- mice reminiscent of cerebellar ataxia. Immunohistochemical analyses of a cerebellum revealed co-localization of HSF1 and calbindin in Purkinje cells. Therefore, we tested the hypothesis of a potential interconnection between HSF1 and calbindin in Purkinje cells. Calbindin levels were analyzed qualitatively and quantitatively by immunohistochemistry and immunoblotting, respectively. While quantitative PCR revealed no differences in calbindin mRNA levels between HSF1+/+ and HSF1-/- mice, calbindin protein levels, however, were significantly decreased in a cerebellum of HSF1-/- mice. A pathway analysis supports the hypothesis of an interconnection between HSF1 and calbindin. In summary, the targeted deletion of HSF1 results in changes of locomotor function associated with changes in cerebellar calbindin protein levels. These findings suggest a role of HSF1 in regular Purkinje cell calcium homeostasis.

Rolling Nagoya mice show ataxia and carry a mutation in the Cacna1a gene, which encodes the pore-forming alpha1 subunit of the Cav2.1 channels. Because an impaired motor function has not been examined during neonatal stages in detail, we employed a battery of tests including assessments of body weight gain, righting reflex, negative geotaxis, hind-limb suspension, and tail suspension using neonatal wild-type, heterozygous, and homozygous rolling mice. We found deterioration of body weight gain after postnatal day 8 (P8) in the homozygous mice, as well as a longer latency time to complete the righting reflex and the negative geotaxis tests after P8. Additionally, the homozygous rolling mice exhibited lower pulling and holding attempts after P8 in the hind-limb suspension test. The mice heterozygous and homozygous for the rolling mutation exhibited muscle fatigue after P10 and P8, respectively, following movement execution tests administered immediately after the first trial, suggesting that gene dosage plays an important role in determining when muscle weakness occurs. The homozygous rolling mice showed hind-limb clasping or touching after P14 during the hind-limb and tail suspension tests. Our results indicate that the gait abnormality of neonatal rolling Nagoya would be due to the combination of muscle weakness and neuronal dysfunction and that the rolling mice could be a useful model for delineating neonatal motor deficiencies.