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 HspS139F mice. Though
sphingolipid levels were not altered in sciatic nerves from HspS139F mice,
ceramides and deoxyceramides, as well as
sphingomyelins (SMs) were elevated in brain tissues from HspS139F mice. Histology was utilized to further characterize HspS139F mice. HspS139F 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, HspS139F mice demonstrated cerebellar
demyelination. Locomotor function, grip strength and gait were examined to define the role of HspS139F in the clinical phenotypes associated with
CMT2F. Gait analysis revealed no differences between HspWT and HspS139F mice. However, both coordination and grip strength were decreased in 3-month-old HspS139F 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.