autophagy and cell death (it seems that in a last attempt of the cells to get rid of the accumulated huntingtin, cleavage of the protein as a result of caspases activation also akes place) The presence of ubiquitin in the aggregates of most poly Q diseases would seem to indicate Image removed due to copyright considerations. that ubiquitination is not impaired, although See Figure 5 in Rechsteiner M, Realini C rates of proteolysis could be affected by Ustrell V. The proteasome activator 11 S REG hanges in the poly Ub chain length, so the (PA28)and class I antigen presentation. Biochem mere presence of Ub doesn't necessarily mean J.2000Jan1;345Pt1:1-15 that an adequate degradation signal has been generated. However certain evidences point out to the hypothesis that poly@ tracts might reduce the rate of polypeptide chain transfer nto the central proteolytic chamber by either nhibiting the ATPases in the 19s subunits of the proteasome or by being difficult to unfold An interesting hypothesis involves alternative proteasome central subunit can associate with Could the functional status of the UPs differ produce the classical 26s to genetIc proteasomes, but instead it can also bind the epigenetic influences unrelated to the donut-shaped 11s REG or pA28 heptamers polyglutamine disease, and can this difference Hybrids binding 11s REGs to one end of the play a role in governing the age of disease 205 proteasome and 19s subunit to the other onset? end of the 20s can also be formed REGo The CAG repeat length in the mutant subunits are thought to play a role in antigen accounts for -70% of the variance of age of presentation by class I MHC molecules and onset for hD (the number of CAG they activate proteasomal hydrolysis following inversely correlated with the age hydrophobic, acidic or basic residues. REGy is onset, suggesting that the rate at which the by contrast, found in the nucleus and is mutant proteins misfold is related to the particularly enriched in nervious tissue. As a length of the poly Q tract). But individual activates hydrolysis after differences in UPS activity could also basic residues but suppress the influence the time it takes for mutant proteins responsible for the cleavage of Gin bond to accumulate in the patient's brain. Thus, the hypothesis is that hybrid 26s pr ate of age-related decline in UPS activity have little difficulty in pumping soluble poly Q could define the efficacy with which the brain tracts into the central proteolytic chamber but if there is impaired cleavage within Gln inf luencing the age of onset of symptoms in an tracts due to bound REGy poly Q peptides ndividual patient would accumulate within the proteasomes, nac tIvaautophagy and cell death (it seems that in a last attempt of the cells to get rid of the accumulated huntingtin, cleavage of the protein as a result of caspases activation also takes place). The presence of ubiquitin in the aggregates of most polyQ diseases would seem to indicate that ubiquitination is not impaired, although rates of proteolysis could be affected by changes in the polyUb chain length, so the mere presence of Ub doesn’t necessarily mean that an adequate degradation signal has been generated. However, certain evidences point out to the hypothesis that polyQ tracts might reduce the rate of polypeptide chain transfer into the central proteolytic chamber by either inhibiting the ATPases in the 19S subunits of the proteasome or by being difficult to unfold. An interesting hypothesis involves alternative forms of the proteasome: The 20S proteasome central subunit can associate with the 19S to produce the classical 26S proteasomes, but instead it can also bind the donut-shaped 11S REG or PA28 heptamers. Hybrids binding 11S REGs to one end of the 20S proteasome and 19S subunit to the other end of the 20S can also be formed. REGα/β subunits are thought to play a role in antigen presentation by class I MHC molecules and they activate proteasomal hydrolysis following hydrophobic, acidic or basic residues. REGγ is, by contrast, found in the nucleus and is particularly enriched in nervious tissue. As a homo-heptamer activates hydrolysis after basic residues but suppress the sites responsible for the cleavage of Gln bonds. The hypothesis is that hybrid 26S proteasomes have little difficulty in pumping soluble polyQ tracts into the central proteolytic chamber, but if there is impaired cleavage within Gln tracts due to bound REGγ, polyQ peptides would accumulate within the proteasomes, inactivating them. Image removed due to copyright considerations. See Figure 5 in Rechsteiner M, Realini C, Ustrell V. The proteasome activator 11 S REG (PA28) and class I antigen presentation. Biochem J. 2000 Jan 1; 345 Pt 1: 1-15. Could the functional status of the UPS differ between individuals due to genetic or epigenetic influences unrelated to the polyglutamine disease, and can this difference play a role in governing the age of disease onset? The CAG repeat length in the mutant accounts for ~70% of the variance of age of onset for HD (the number of CAG repeats is inversely correlated with the age of disease onset, suggesting that the rate at which the mutant proteins misfold is related to the length of the polyQ tract). But individual differences in UPS activity could also influence the time it takes for mutant proteins to accumulate in the patient’s brain. Thus, the rate of age-related decline in UPS activity could define the efficacy with which the brain handles the mutant proteins, thereby influencing the age of onset of symptoms in an individual patient