A novel HSPB1 S139F mouse model of Charcot-Marie-Tooth Disease

Charcot-Marie-Tooth Disease (CMT) is a commonly inherited peripheral polyneuropathy. Clinical manifestations for this disease include symmetrical distal polyneuropathy, altered deep tendon reflexes, distal sensory loss, foot deformities, and gait abnormalities. Genetic mutations in heat shock proteins have been linked to CMT2. Specifically, mutations in the heat shock protein B1 (HSPB1) gene encoding for heat shock protein 27 (Hsp27) have been linked to CMT2F and distal hereditary motor and sensory neuropathy type 2B (dHMSN2B) subtype. The goal of the study was to examine the role of an endogenous mutation in HSPB1 in vivo and to define the effects of this mutation on motor function and pathology in a novel animal model. As sphingolipids have been implicated in hereditary and sensory neuropathies, we examined sphingolipid metabolism in central and peripheral nervous tissues in 3-month-old Hsp mice. Though sphingolipid levels were not altered in sciatic nerves from Hsp mice, ceramides and deoxyceramides, as well as sphingomyelins (SMs) were elevated in brain tissues from Hsp mice. Histology was utilized to further characterize Hsp mice. Hsp mice exhibited no alterations to the expression and phosphorylation of neurofilaments, or in the expression of acetylated α-tubulin in the brain or sciatic nerve. Interestingly, Hsp mice demonstrated cerebellar demyelination. Locomotor function, grip strength and gait were examined to define the role of Hsp in the clinical phenotypes associated with CMT2F. Gait analysis revealed no differences between Hsp and Hsp mice. However, both coordination and grip strength were decreased in 3-month-old Hsp mice. Together these data suggest that the endogenous S139F mutation in HSPB1 may serve as a mouse model for hereditary and sensory neuropathies such as CMT2F.