Type 2L: Abnormal small heat shock protein interactions involving neuropathy-ass

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FASEB J. 2006 Aug 25

Abnormal small heat shock protein interactions involving neuropathy-

associated HSP22 (HSPB8) mutants.

Fontaine JM, Sun X, Hoppe AD, Simon S, Vicart P, Welsh MJ, Benndorf

R.

Departments of *Cell and Developmental Biology, andMicrobiology and

Immunology, University of Michigan Medical School, Ann Arbor,

Michigan, USA; and EA 300 Stress et Pathologies du Cytosquelette,

Universite Paris 7, UFR de Biochimie, Paris, France.

Two mutations (K141E, K141N) in the small heat shock protein (sHSP)

HSP22 (HSPB8) are associated with the inherited peripheral motor

neuron disorders distal hereditary motor neuropathy type II and

axonal Charcot-Marie-Tooth disease type 2L.

HSP22 is known to form homodimers, heterodimers with other sHSPs, and

larger oligomers. In an effort to elucidate the cellular basis for

these diseases, we have determined the ability of mutant HSP22 to

interact with itself, with wild-type HSP22, and with other sHSPs that

are abundant in neurons. Using the yeast two-hybrid method,

quantitative fluorescence resonance energy transfer in live cells,

and cross-linking, we found aberrantly increased interactions of

mutant HSP22 forms with themselves, with wild-type HSP22, and with

the other sHSPs, alphaB-crystallin, and HSP27. Interaction with HSP20

was not affected by the mutations.

The data suggest that each mutant form of HSP22 has a characteristic

pattern of abnormal interaction properties. A mutation (S135F) in

HSP27 that is also associated with these disorders showed increased

interaction with wild-type HSP22 also, suggesting linkage of these

two etiologic factors, HSP22 and HSP27, into one common pathway.

Increased interactions involving mutant sHSPs may be the molecular

basis for their increased tendency to form cytoplasmic protein

aggregates, and for the occurrence of the associated neuropathies.