title: Are Huntington's and polyglutamine-based ataxias proteasome storage diseases?
abstract: To date, 10 neurological diseases, including Huntington's and several ataxias, are caused by a lengthening of glutamine (Q) tracts in various proteins. Even though the Q expansions arise in unrelated proteins, the diseases share three striking features: (1) 35 contiguous glutamines constitutes the pathological threshold for 9 of the 10 diseases; (2) the Q-expanded proteins are expressed in many tissues, yet pathology is largely restricted to neurons; and (3) the Q-expanded proteins or fragments thereof form nuclear inclusions that also contain ubiquitin, proteasomes and chaperones. Our studies of the proteasome activator REGgamma suggest a possible explanation for these shared properties. REGgamma is highly expressed in brain, located in the nucleus and actually suppresses the proteasome active sites principally responsible for cleaving glutamine-MCA bonds. These observations coupled with reports that peptides longer than 35 residues, the polyQ pathology threshold, are unable to diffuse out of the proteasome suggest the following hypothesis. Proteins containing long glutamine tracts are efficiently pumped into REGgamma-capped 26S proteasomes, but REGgamma suppression of cleavage after glutamine produces polyQ fragments too long to diffuse out of the 20S proteolytic core thereby inactivating the 26S proteasome. In effect, we hypothesize that the polyQ pathologies may be proteasomal storage diseases analogous to disorders of lysosome catabolism.
authors.affiliation: Department of Biochemistry, University of Utah, 50 N Medical Drive, Salt Lake City, UT 84132, USA.
authors.forename: Geoffrey M
authors.initials: GM
authors.lastname: Goellner
authors.forename: Martin
authors.initials: M
authors.lastname: Rechsteiner
mesh_terms: D000818:Animals; D001259:Ataxia / Q000378:metabolism* / Q000628:therapy; D001324:Autoantigens; D003546:Cysteine Endopeptidases / Q000378:metabolism*; D005973:Glutamine / Q000378:metabolism*; D006816:Huntington Disease / Q000378:metabolism* / Q000628:therapy; D051379:Mice; D009097:Multienzyme Complexes / Q000378:metabolism*; D009687:Nuclear Proteins / Q000378:metabolism; D046988:Proteasome Endopeptidase Complex; D011506:Proteins / Q000378:metabolism; D025801:Ubiquitin / Q000378:metabolism
chemical_list: D001324:Autoantigens; C099558:Ki antigen; D009097:Multienzyme Complexes; D009687:Nuclear Proteins; D011506:Proteins; C108663:REG proteasome activator subunit beta; D025801:Ubiquitin; D005973:Glutamine; D003546:Cysteine Endopeptidases; D046988:Proteasome Endopeptidase Complex