CMT 1X : Axonal Pathology Precedes Demyelination in a Mouse Model of X-Linked De

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J Neuropathol Exp Neurol. 2010 Aug 1

Axonal Pathology Precedes Demyelination in a Mouse Model of X-Linked

Demyelinating/Type I Charcot-Marie Tooth Neuropathy.

Vavlitou N, Sargiannidou I, Markoullis K, Kyriacou K, Scherer SS, Kleopa KA.

From the Neuroscience Laboratory and Neurology Clinics (NV, IS, KM, KAK) and

Department of Electron Microscopy and Molecular Pathology (KK), The Cyprus

Institute of Neurology and Genetics, Nicosia, Cyprus; and Department of

Neurology, University of Pennsylvania School of Medicine, Philadelphia,

Pennsylvania (SSS).

Abstract

The X-linked demyelinating/type I Charcot-Marie-Tooth neuropathy (CMT1X) is an

inherited peripheral neuropathy caused by mutations in GJB1, the gene that

encodes the gap junction protein connexin32. Connexin32 is expressed by

myelinating Schwann cells and forms gap junctions in noncompact myelin areas,

but axonal involvement is more prominent in X-linked compared with other forms

of demyelinating Charcot-Marie-Tooth disease.

To clarify the cellular and molecular mechanisms of axonal pathology in CMT1X,

we studied Gjb1-null mice at early stages (i.e. 2-4 months old) of the

neuropathy, when there is minimal or no demyelination. The diameters of large

myelinated axons were progressively reduced in Gjb1-null mice compared with

those in wild-type littermates.

Furthermore, neurofilaments were relatively more dephosphorylated and more

densely packed starting at 2 months of age. Increased expression of beta-amyloid

precursor protein, a marker of axonal damage, was also detected in Gjb1-null

nerves.

Finally, fast axonal transport, assayed by sciatic nerve ligation experiments,

was slower in distal axons of Gjb1-null versus wild-type animals with reduced

accumulation of synaptic vesicle-associated proteins.

These findings demonstrate that axonal abnormalities including impaired

cytoskeletal organization and defects in axonal transport precede demyelination

in this mouse model of CMT1X.