CMT 2L: Mutant HSPB8 causes motor neuron specific neurite degeneration

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Mutant HSPB8 causes motor neuron specific neurite degeneration.

Hum Mol Genet. 2010 Jun 10

Irobi J, Almeida-Souza L, Asselbergh B, De Winter V, Goethals S, Dierick I,

Krishnan J, Timmermans JP, Robberecht W, De Jonghe P, Van Den Bosch L, Janssens

S, Timmerman V.

Abstract

Missense mutations (K141N and K141E) in the alpha-crystallin domain of the small

heat shock protein HSPB8 (HSP22) cause distal hereditary motor neuropathy

(distal HMN) or Charcot-Marie-Tooth neuropathy type 2L (CMT2L). The mechanism

through which mutant HSPB8 leads to a specific motor neuron disease phenotype is

currently unknown.

To address this question, we compared the effect of mutant HSPB8 in primary

neuronal and glial cell cultures. In motor neurons, expression of both HSPB8

K141N and K141E mutations clearly resulted in neurite degeneration, as

manifested by a reduction in number of neurites per cell, as well as in a

reduction in average length of the neurites.

Furthermore, expression of the K141E (and to a lesser extent, K141N) mutation

also induced spheroids in the neurites. We did not detect any signs of apoptosis

in motor neurons, showing that mutant HSPB8 resulted in neurite degeneration

without inducing neuronal death.

While overt in motor neurons, these phenotypes were only very mildly present in

sensory neurons and completely absent in cortical neurons. Also glial cells did

not show an altered phenotype upon expression of mutant HSPB8.

These findings show that despite the ubiquitous presence of HSPB8, only motor

neurons appear to be affected by the K141N and K141E mutations which explains

the predominant motor neuron phenotype in distal HMN and CMT2L.