Charcot-Marie-Tooth (CMT) disease is a common disorder of the peripheral nervous system characterised by progressive weakness and atrophy of distal muscles, sensory loss and foot deformities. Depending on the predominant neurological defect, it is classified as Type 1 CMT (demyelination), Type 2 CMT (axonal loss) or distal hereditary motor neuropathy (HMN; mainly affecting motor axons). Among the ∼40 genes linked to the disease is HSPB1, which can cause Type 2 CMT or distal HMN, depending on the mutation. To investigate the underlying mechanisms, d’Ydewalle et al. created two transgenic mouse strains expressing CMT-associated mutant forms of HSPB1 specifically in neurons: S135F, causing symptoms resembling Type 2 CMT, and P182L, causing symptoms resembling distal HMN. In addition to neurological defects, both strains displayed axonal transport deficits caused by decreased α-tubulin acetylation (a cue for anchoring of molecular motors) in peripheral nerves. Inhibiting the histone deacetylase HDAC6, the primary enzyme that deacetylates α-tubulin, restored axonal transport and abrogated disease symptoms in HSPB1S135F-expressing mice. So, dysregulated α-tubulin acetylation might play a role in the pathology of CMT and other heritable peripheral neuropathies, opening up new avenues for treatment.

d’Ydewalle
C.
,
Krishnan
J.
,
Chiheb
D. M.
,
Van Damme
P.
,
Irobi
J.
,
Kozikowski
A. P.
,
Vanden Berghe
P.
,
Timmerman
V.
,
Robberecht
W.
,
Van Den Bosch
L.
(
2011
).
HDAC6 inhibitors reverse axonal loss in a mouse model of mutant HSPB1-induced Charcot-Marie-Tooth disease
.
Nat. Med.
17
,
968
974
.

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