Aggregate-centered redistribution of proteins by mutant huntingtin.
Huntingtin is a widely expressed 350-kDa cytosolic multidomain of unknown function. Aberrant expansion of the polyglutamine tract located in the N-terminal region of huntingtin results in Huntington's disease. The presence of insoluble huntingtin inclusions in the brains of patients is one of the hallmarks of Huntington's disease. Experimentally, both full-length huntingtin and N-terminal fragments of huntingtin with expanded polyglutamine tracts trigger aggregate formation. Here, we report that upon the formation of huntingtin aggregates; endogenous cytosolic huntingtin, Hsc70/Hsp70 (heat shock protein and cognate protein of 70kDa) and syntaxin 1A become aggregate-centered. This redistribution suggests that these proteins are eventually depleted and become unavailable for normal cellular function. These results indicate that the cellular targeting of several key proteins are altered in the presence of mutant huntingtin and suggest that aggregate depletion of these proteins may underlie, in part, the sequence of disease progression.
Swayne
Leigh Anne
LA
Hotchkiss Brain Institute, Department of Physiology and Biophysics, University of Calgary, Calgary, Alta., Canada T2N 4N1.
Braun
Janice E A
JE
D000818:Animals; D002478:Cells, Cultured; D018840:HSP70 Heat-Shock Proteins / Q000378:metabolism*; D006801:Humans; D000071058:Huntingtin Protein; D007668:Kidney / Q000378:metabolism*; D051379:Mice; D009154:Mutation; D009419:Nerve Tissue Proteins / Q000235:genetics* / Q000378:metabolism*; D009474:Neurons / Q000378:metabolism*; D009687:Nuclear Proteins / Q000235:genetics* / Q000378:metabolism*; D013347:Subcellular Fractions / Q000378:metabolism*
D018840:HSP70 Heat-Shock Proteins; C086055:HTT protein, human; D000071058:Huntingtin Protein; D009419:Nerve Tissue Proteins; D009687:Nuclear Proteins