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Edited by Sue Hengren Wickner, National Institutes of Health, Bethesda, MD, and approved August 1, 2006 (received for review March 22, 2006)
Article Figures & SI
Figures
- Fig. 1.
Nucleation-dependent polymerization mechanism of polyGln aggregation. Formation of nucleus N* from bulk-phase monomer M a is modeled as a reversible, highly unfavorable reaction. Once formed, the metastable N* can either disintegrate back to the monomer pool or elongate by adding M b molecules to form N*+1, N*+2, etc., and by doing so stabilize the system. The term M b signifies the monomer pool capable of supporting elongation. In most amyloid systems, M b is identical to M a, but, as shown in this paper, M b can be an expanded pool that includes other polyGln sequences. Previously, we showed that the number of molecules of polyGln comprising N* (called critical nucleus, or n*) is equal to 1 for nucleation of polyGln aggregation (15); the general aspects of theory and interpretation discussed in this work, however, are independent of the molecularity of N*.
- Fig. 2.
The effect of a short polyGln peptide on the nucleation of a polyGln of pathological length. (a) PolyGln Q47 was incubated at 37°C at 1.8 μM, either alone (○) or in the presence of various concentrations of Q20: 14 μM (◇), 24 μM (◆), 36 μM (△), 44 μM (▲), and 54 μM (■). The disappearance of Q47 from the soluble phase is shown on a relative basis for each reaction mixture. (b) t 2 plots (14) of the nucleation kinetics of various concentrations of Q47 in the presence of 18 μM Q20. Starting concentrations of Q47 were 13.2 (○), 10.8 (●), 8.6 (△), 6.4 (▲), and 4.5 (◆) μM. (c) Concentration dependence of nucleation kinetics, plotting the logarithm of the slopes of the t 2 plots from b versus log[Q47]. The slope m of the linear regression fit is 3.2, R 2 = 0.9881; N* is calculated to be 1.2 (N* = m − 2) (15).
- Fig. 3.
The role of repeat length on the augmentation of Q47 aggregation nucleation by shorter polyGln sequences. Samples of 1.5–2.0 μM Q47 were incubated either alone (○) or with 20 μM polyGln peptides of various repeat lengths: Q10 (◇), Q15 (◆), Q20 (△), Q25 (▲), Q29 (□), Q33 (■), or Q40 (●). The disappearance of Q47 from the soluble phase is shown on a relative basis for each reaction mixture.
- Fig. 4.
The role of elongation kinetics in aggregation nucleation. (a) Rates of elongation of 2.3 μg/ml Q47 amyloid fibrils by 17 μM monomeric polyGln plotted against the repeat length of the monomeric polyGln. (Inset) Pseudofirst-order rate plot for the elongation of 17 μM Q20; because the molar concentration of fibrils does not change in a simple fibril elongation reaction, elongation kinetics are pseudofirst-order (39), yielding a pseudofirst-order rate constant that is an amalgam of the true second-order rate constant and the molar concentration of fibrils. (b) A plot of the slope of the t 2 plot for Q47 nucleation (Fig. 3) with respect to the square of the rate constants k +, describing the elongation of each short polyGln peptide (from a). [We used the square of the rate constant here because of the dependence of nucleation kinetics on the second power of the elongation rate, as shown in the equation Δ = 1/2k + 2 Kn * c (n*+2) t 2 (14, 15).]
- Fig. 5.
Coexpression of Httex1p-Q20p increases formation of nuclear inclusions and toxicity of Httex1p-Q93p. (a) Confocal images of Drosophila eye expressing polyGln transgenes in adult photoreceptor neurons. Htt accumulation is green, rhabdomeres of photoreceptor neurons are red by anti-actin staining, and photoreceptor nuclei are blue by staining with anti-elav antibody. The first four columns of photographs show cross-sections at days 5 and 6. (Scale bar: 10 μM.) The last three columns of photographs show longitudinal sections through the eye at day 6. (Scale bar: 20 μM.) Extensive staining of cytoplasmic Htt is seen at day 5 and is primarily converted to nuclear staining in 6-day-old flies. At each time point, where Q20 is coexpressed with Q93, an increase in the number of visible inclusions is observed. No aggregates are observed with Q20 alone. (b) The number of photoreceptor nuclei with visible inclusions in 5-, 6-, and 10-day-old flies (d5, d6, and d10, respectively). The fraction of nuclei with inclusions at days 5 and 6 is increased when Q20 is coexpressed; however, the percentage of nuclei with inclusions with and without Q20 coexpression plateaus by day 10. The percentage of nuclear accumulation was calculated as Htt-positive nuclei per all nuclei per field [∗, P < 0.025 (0.0239); ∗∗, P < 0.015 (0.0145)]. (c) Pathology is evaluated by comparing the number of rhabdomeres per ommatidium in 8-day-old (d8) and 12-day-old (d12) flies [∗∗∗, P < 0.0015 (0.00141)]. No neurotoxicity is observed up to day 8, but toxicity is evident by day 12 and is increased by the presence of Q20.
Normal-repeat-length polyglutamine peptides accelerate aggregation nucleation and cytotoxicity of expanded polyglutamine proteins
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