Skuodas S , Clemons A , Hayes M , Goll A , Zora B , Weeks DL , Phillips BT , Fassler JS .

T32 GM007337 NIGMS NIH HHS , R01 GM114007 NIGMS NIH HHS , R01 GM124063 NIGMS NIH HHS , P40 OD010440 NIH HHS , IOS-1456941 National Science Foundation

	FIGURE 1:. Simplified overview of aggregation pathways. Intrinsically disordered monomeric proteins self-associate to create an assortment of transient higher-order structures including liquid droplets, hydrogels, and the highly stable solid amyloids. These structures are differentially detected by stains such as ThioT and X-34 and conformer specific antibodies including the oligomer-specific A11 antibody and the fiber-specific OC antibody. Modified from Hayes et al. (2018) and Wu and Fuxreiter (2016).
	FIGURE 2:. Endogenous C. elegans amyloids. (A) Hermaphrodite gonad cartoon showing germline and early embryos. (B, C) A11 antibody positive puncta (green, arrows) in a 1-cell zygote (B) and an eight-cell embryo (C). (B’, C’) γ-Tubulin staining (red) shows these puncta colocalize with centrosomes. (D) A similar pattern is also seen with the OC antibody (green). (E, F) A11 (green) stains nuclear membranes in germline oocytes (arrowheads in E), all cells in early embryos (E, inset arrowheads), and select cells in late embryos (arrowheads in F). Cells in F identified as PGCs by the PES-1 (red) expression in the adjacent somatic gonadal precursors (arrows). (G) Noncentrosomal A11 puncta in the P2 cell that become visible with longer exposure (black arrows). (A–F) Blue, DAPI-stained DNA. (H–H’’’) A subdomain of C. elegans P granules displays amyloid character. Embryonic P cell stained for A11 (green in H), P granule marker, PGL-1 (red in H’), and DAPI-stained DNA (blue in H’’). (H–H’’’) Arrows denote P granules that are A11 negative, while arrowheads denote P granules that are A11-positive; c, centrosome. Frequencies of depicted phenotypes are as follows: (B,C, E, G) 100% n > 100; (D) 100% n = 63; (F) 100% n = 17; (H and H’’) 100% n > 100; (H’’’) 77% of P granules are positive for A11 n > 100. Scale bar: 12 um in B–D and G; 20 um in E; 44 um in E, inset; 21 µM in F; and 6 µM in H–K.
	FIGURE 3:. Effects of HSP104 misexpression in C. elegans. (A–J) Typical control-injected embryos after GFP mRNA injection (A, B) or buffer injection (C–E) showing normal distribution of A11 on oocyte nuclear membrane (A) and embryonic nuclear membranes and centrosomes at the 1- (B), 4- (C), 16- (D), and 32-cell stage (E). (F–J) Corresponding DAPI-stained DNA images of A–E. (K–N) A11-stained oocyte (K) and embryos (L–N) after potentiated HSP104 mRNA injections. (K) Oocyte exhibiting dim nuclear membrane A11 but additional A11 nuclear puncta (arrowheads). (L) Dividing one-cell embryo with dim centrosomal (arrows) and nuclear membrane A11. (M) Four- to eight-cell embryo with dim and misshapen centrosomes (arrows). (N) Thirty-two-cell embryo with variably dim centrosomes (arrows). (O–R) Corresponding DAPI-stained DNA images of K–N. (S–U) A11-stained embryos after mutant HSP104 mRNA injections. (S, T) Aberrant three-cell embryo with two cells in telophase and one in anaphase (S) and six-cell embryo (T) but exhibiting normal A11 patterns. (U) Thirty-two-cell embryo showing normal A11 and cell division patterns after mutant HSP104 mRNA injection. (V–X) Corresponding DAPI-stained DNA images of (S–U). (Y–Z) Sixteen-cell embryo with dim centrosomal A11 puncta (arrows) after injection of wild-type Hsp104 protein. (Y’) Same A11 sample as Y, but with 70% brighter exposure. (Z) Corresponding DAPI-stained DNA image of Y and Y’. Frequencies of depicted phenotypes are as follows: (A–E) 97% n = 30; (K–N) 40% abnormal A11 patterning and 30% defective cell division defects, n = 110; (S–U) 99% normal A11 pattern n = 82; (S, T) 26% abnormal cell division defects n = 82; (U) 74% normal cell division pattering n = 82; (Y–Z) 41% abnormal A11 n = 22. Scale bar, 10 µm
	FIGURE 4:. Phenotypic analysis of Arb1-depleted strains. (A) Western analysis using α-FLAG antibody to gauge levels of Arb1 protein expressed from an arb1 deletion strain carrying the UASG-ARB1-d depletion construct [pDH25.1] (Dong et al., 2005) cultivated in galactose or glucose, relative to Arb1 protein levels from pDH29 (Dong et al., 2005), in which the ARB1 gene is expressed under the control of its own promoter. (B) Growth of the arb1 deletion strain carrying pDH25.1 (ARB1-d) or pDH22 (ARB1) (Dong et al., 2005) after serial dilutions on YPD (glucose) or YP Gal plates (galactose). (C) Arb1 depletion causes temperature and HB sensitivity. YPD plates containing the indicated concentrations of HB were incubated at 26, 30, or 37°C for 2–5 d as appropriate. (D) Arb1 depletion strain phenotypes are exacerbated by the absence of the New1 disaggregase. Strains were grown to early log phase in YP Gal Raff media at 30°C and serial dilutions spotted on YP Gal Raff (Gal Raff) or YPD (glucose) plates with 0 or 30 μg/ml HB which were incubated at 26°C (4 d) or 18°C (7 d). arb1δ [pDH25.1] (YDH226) (Dong et al., 2005); hsp104δ (JF2498); new1δ arb1δ [pDH25.1] (JF2510); hsp104δ arb1δ [pDH25.1] (JF2511).
	FIGURE 5:. Arb1 depletion delays the dissolution of heat-denatured FFL-GFP aggregates. (A) Quantitation of the percentage of cells with aggregates remaining after 30, 60, or 90 min of recovery time following heat treatment. Strains of different genotypes, all carrying the p426Met25-FFL-GFP aggregation reporter plasmid, were grown to early log phase at 30°C in selective media with galactose and raffinose as carbon sources. Cultures were then switched to selective media with glucose as carbon source for 2.5 h to deplete Arb1 and then to media lacking methionine for 1.5 h to express the FFL-GFP gene. Finally, cultures were heat treated (25 min, 42°C) and allowed to recover at 30°C for the indicated times before imaging. A minimum of 100 cells of each genotype were tabulated for each time point. Data for each strain and time point are the averages of three to six trials involving at least three transformants. Error bars are the SD of the means. ANOVA analysis with Tukey post hoc tests were used to determine the significance of observed difference in phenotype of the wild-type strain relative to strains of all other genotypes (excluding hsp104δ) at each time point (30′, 60′, and 90′). The ARB1-d (glucose) sample was significantly different (**P < 0.01) from the wild-type strain at all three times. Other comparisons (not indicated in the figure for clarity) were nonsignificant with the exception of new1 and ARB1-d (glucose and galactose) (p < 0.01, 90′) and the arb1(ARB1) control and ARB1-d (glucose and galactose (p < 0.01, 90′). (B) Representative images for strain YDH226 under Arb1 depletion (glucose) and Arb1 expressing conditions (galactose) at indicated times following heat shock. Strains were wild type (BY4730), UASG-ARB1 (YDH226), new1δ (JF2475), and hsp104δ (JF2473) transformed with the pRS426 UASMET25FFL-GFP plasmid.
	FIGURE 6:. Arb1 depletion causes a defect in maintenance (propagation) of Htt-Q97 amyloids. (A) Percentage of cells maintaining Htt-Q97 –GFP aggregates in the presence or absence of candidate chaperones. Cells were grown to early log phase in selective media containing galactose (up arrow) at 30°C at which point the culture was split and galactose was washed out and replaced with selective media containing glucose (down arrow) prior to growth for another 4 h. Data for each strain are the averages of three transformants and two to three trials. Error bars are the SD of the means. Strains were arb1δ with pDH22 (ARB1), new1δ (JF2475), UASG-ARB1-d (arb1δ with pDH25, YDH226) (Dong et al., 2005), and hsp104δ (JF2473). All strains carried the p416-Htt-Q97-GFP plasmid. The significance of differences in phenotype between the wt strain and strains of other genotypes was assessed by ANOVA-Tukey HSD analysis (**p < 0.01). (B, C) Representative SDD-AGE (B) and SDS–PAGE (C) anti-GFP Western analysis of extracts prepared from haploid strains wt (BY4730), hsp104δ (JF2473), new1 δ (JF2475), and the arb1δ strain YDH226 carrying the pDH25.1 Arb1 depletion plasmid. In later experiments, an arb1δ (pARB1) strain was also included (not shown) as it proved to be a better control than the galactose grown pDH25.1, which expresses reduced levels of Arb1 due to protein destabilization (Dong et al., 2005) (Figure 4 and Supplemental Figure S4B). Three transformants were analyzed in each experiment. Approximately equal loading of extracts across lanes was evaluated by quantitation of the SDS–PAGE gel following REVERT (LI-COR) staining. In the SDD-AGE experiment, wild-type extracts were loaded at 0.5× so that the signal was more even across the blot. The difference in loading was accounted for in the analysis. (D) Aggregate load was calculated as the percentage of aggregated GFP signal over the total signal (SDS–PAGE + SDD-AGE). Significance was evaluated by ANOVA-Tukey HSD analysis (Tukey, 1949) per experiment (three transformants) to reduce the impact of technical (extract to extract) variability and keep the focus on biological variability. The hsp104δ was significantly different (P < 0.01) from all other strains. The wt and the arb1δ(pARB1) control strains were significantly different (*p < 0.05) from all other strains. Differences between the new1δ and ARB1-d strains were not significant.
	FIGURE 7:. Aggregate processing phenotypes in yeast strains with low levels of Arb1 or lacking Gcn20/Abcf3 are partially complemented by animal ABCF genes. (A) Plasmids carrying each of three different animal ABCF2 cDNAs under yeast PADH1 control (Xl, X. laevis [high copy[, Ce, Caenorhabditis elegans [high copy], and Hs, Homo sapiens [low copy]) were introduced into the ARB1-DAmP/arb1Δ diploid strain (JF2639) carrying the pRS426 UASMET25FFL-GFP aggregation reporter plasmid and resolubilization following heat treatment monitored over time (0, 60, 90, and 120 min). (B) As for A, resolubilization of the FFL-GFP reporter was examined in the ARB1-DAmP/arb1Δ diploid strain (JF2639) expressing Xenopus ABCF2 (pSS2182) or two versions of the the corresponding Walker Domain (Walker A-2, K431W) mutant (pSS2198 and pSS2199). (C) Similar to A, resolubilization of the FFL-GFP reporter was examined in the ARB1-DAmP/arb1Δ diploid strain (JF2639) expressing human ABCF1, ABCF2, and ABCF3 cDNAs. For data in A–C, a minimum of 100 cells of each genotype were tabulated for each time point, and data for each strain and time point are the averages of three to six trials involving at least three transformants. (D) Amyloid disaggregation was evaluated as described in the legend to Figure 6. Strains were wt (BY4730), hsp104 (JF2473), and gcn20 (from the deletion collection). High and low copy human ABCF1, ABCF2, and ABCF3 expression plasmids as well as the yeast ARB1 plasmid, pDH129, were introduced into the gcn20Δ strain carrying the amyloid reporter plasmid, p416-Htt-Q97-GFP, and evaluated for their effect on amyloid propagation. For all experiments, significance was determined using ANOVA-Tukey HSD analysis (Tukey, 1949) (*p < 0.05, **p < 0.01). In A, the resolubilization phenotype of DAmP/arb1Δ strains (carrying an empty vector) was complemented by expression of animal ABCF2 genes at 90 and 120 min. In B, complementation by expression of the Xenopus Walker domain mutant (abcf2-K431W) was significantly reduced relative to expression of the wild-type Xenopus ABCF2. In C, complementation by the human ABCF1 and ABCF2 plasmids (but not ABCF3) was significantly better than the same DAmP/arb1Δ strain carrying an empty vector. In D, wild-type aggregation values were significantly different from hsp104Δ, gcn20Δ, and gcn20Δ + pARB1. In addition, aggregation values for the gcn20 strain carrying HsABCF1 (low and high copy), HsABCF2 (high copy), and HsABCF3 (low and high copy) were significantly different from gcn20Δ + vector and gcn20Δ = pARB1. (**p < 0.01; *p < 0.05).
	FIGURE 8:. De novo synthesis of the localized mRNA ABCF2 is required for gastrulation and embryonic development in Xenopus. (A) Oligonucleotide-mediated reduction in ABCF2 mRNA relative to the Histone H4 control as assayed by rtPCR (left). RNA was isolated from embryos 2 h postinjection with the indicated levels of DMED-modified anti-ABCF2 oligonucleotide. (B) A comparison of uninjected and injected embryos assayed 12 h after injection shows the dose-dependent inhibition of formation of the blastopore lip and sequential progression toward gastrulation. (C) Spatially directed reduction of ABCF2 shows the importance of localized maternal inheritance of ABCF2 mRNA and the ability of human ABCF2 to replace lost maternal ABCF2 mRNA. Injection of DMED-modified anti-ABCF2 oligonucleotide was delayed until embryos had completed three cleavage cycles, forming an eight-cell embryo with visually distinct animal and vegetal tiers of cells; 0.1 ng of oligonucleotide, human ABCF2 mRNA, or both were injected into either the four animal hemisphere cells or four vegetal hemisphere cells as indicated. Clusters of embryos were photographed at the indicated time. By 24 h, the delay in cell cleavage and failure to gastrulate can be seen in embryos injected with anti-ABCF2 alone when injections were directed to the animal hemisphere tier of cells. Scale bars in B and C: 1 mm.
	FIGURE 9:. C. elegans ABCF loss of function causes germline arrest and increased amyloid production. (A) Top, experimental scheme to assess ABCF loss of function effects on development. Bottom, phenotypic quantitation. (B–E) Wild-type (B, D) or abcf-2(ok2388) (C, E) adult germlines exposed to control (B, C) or abcf-1 (D, E) RNAi and stained for amyloid oligomers (A11, green) and DNA (DAPI, blue). Frequencies of depicted phenotypes are as follows: (B) 100% n > 100; (C) 100% n = 20; (D) 100% n = 30; (E) 71% (n = 17) of germlines showed expansion of A11-positive structures into the distal germline and 76% (n = 17) showed enlarged or fused oocytes. Arrowheads denote A11 puncta. Arrows in E denote expanded A11 puncta compared with the localization in abcf-1 single loss of function animals (arrowheads in D and E). EV, empty RNAi vector. Scale bar, 50 µm.
	FIGURE 2:. Endogenous C. elegans amyloids. (A) Hermaphrodite gonad cartoon showing germline and early embryos. (B, C) A11 antibody positive puncta (green, arrows) in a 1-cell zygote (B) and an eight-cell embryo (C). (B’, C’) γ-Tubulin staining (red) shows these puncta colocalize with centrosomes. (D) A similar pattern is also seen with the OC antibody (green). (E, F) A11 (green) stains nuclear membranes in germline oocytes (arrowheads in E), all cells in early embryos (E, inset arrowheads), and select cells in late embryos (arrowheads in F). Cells in F identified as PGCs by the PES-1 (red) expression in the adjacent somatic gonadal precursors (arrows). (G) Noncentrosomal A11 puncta in the P2 cell that become visible with longer exposure (black arrows). (A–F) Blue, DAPI-stained DNA. (H–H’’’) A subdomain of C. elegans P granules displays amyloid character. Embryonic P cell stained for A11 (green in H), P granule marker, PGL-1 (red in H’), and DAPI-stained DNA (blue in H’’). (H–H’’’) Arrows denote P granules that are A11 negative, while arrowheads denote P granules that are A11-positive; c, centrosome. Frequencies of depicted phenotypes are as follows: (B,C, E, G) 100% n > 100; (D) 100% n = 63; (F) 100% n = 17; (H and H’’) 100% n > 100; (H’’’) 77% of P granules are positive for A11 n > 100. Scale bar: 12 um in B–D and G; 20 um in E; 44 um in E, inset; 21 µM in F; and 6 µM in H–K.
	FIGURE 3:. Effects of HSP104 misexpression in C. elegans. (A–J) Typical control-injected embryos after GFP mRNA injection (A, B) or buffer injection (C–E) showing normal distribution of A11 on oocyte nuclear membrane (A) and embryonic nuclear membranes and centrosomes at the 1- (B), 4- (C), 16- (D), and 32-cell stage (E). (F–J) Corresponding DAPI-stained DNA images of A–E. (K–N) A11-stained oocyte (K) and embryos (L–N) after potentiated HSP104 mRNA injections. (K) Oocyte exhibiting dim nuclear membrane A11 but additional A11 nuclear puncta (arrowheads). (L) Dividing one-cell embryo with dim centrosomal (arrows) and nuclear membrane A11. (M) Four- to eight-cell embryo with dim and misshapen centrosomes (arrows). (N) Thirty-two-cell embryo with variably dim centrosomes (arrows). (O–R) Corresponding DAPI-stained DNA images of K–N. (S–U) A11-stained embryos after mutant HSP104 mRNA injections. (S, T) Aberrant three-cell embryo with two cells in telophase and one in anaphase (S) and six-cell embryo (T) but exhibiting normal A11 patterns. (U) Thirty-two-cell embryo showing normal A11 and cell division patterns after mutant HSP104 mRNA injection. (V–X) Corresponding DAPI-stained DNA images of (S–U). (Y–Z) Sixteen-cell embryo with dim centrosomal A11 puncta (arrows) after injection of wild-type Hsp104 protein. (Y’) Same A11 sample as Y, but with 70% brighter exposure. (Z) Corresponding DAPI-stained DNA image of Y and Y’. Frequencies of depicted phenotypes are as follows: (A–E) 97% n = 30; (K–N) 40% abnormal A11 patterning and 30% defective cell division defects, n = 110; (S–U) 99% normal A11 pattern n = 82; (S, T) 26% abnormal cell division defects n = 82; (U) 74% normal cell division pattering n = 82; (Y–Z) 41% abnormal A11 n = 22. Scale bar, 10 µm
	FIGURE 4:. Phenotypic analysis of Arb1-depleted strains. (A) Western analysis using α-FLAG antibody to gauge levels of Arb1 protein expressed from an arb1 deletion strain carrying the UASG-ARB1-d depletion construct [pDH25.1] (Dong et al., 2005) cultivated in galactose or glucose, relative to Arb1 protein levels from pDH29 (Dong et al., 2005), in which the ARB1 gene is expressed under the control of its own promoter. (B) Growth of the arb1 deletion strain carrying pDH25.1 (ARB1-d) or pDH22 (ARB1) (Dong et al., 2005) after serial dilutions on YPD (glucose) or YP Gal plates (galactose). (C) Arb1 depletion causes temperature and HB sensitivity. YPD plates containing the indicated concentrations of HB were incubated at 26, 30, or 37°C for 2–5 d as appropriate. (D) Arb1 depletion strain phenotypes are exacerbated by the absence of the New1 disaggregase. Strains were grown to early log phase in YP Gal Raff media at 30°C and serial dilutions spotted on YP Gal Raff (Gal Raff) or YPD (glucose) plates with 0 or 30 μg/ml HB which were incubated at 26°C (4 d) or 18°C (7 d). arb1Δ [pDH25.1] (YDH226) (Dong et al., 2005); hsp104Δ (JF2498); new1Δ arb1Δ [pDH25.1] (JF2510); hsp104Δ arb1Δ [pDH25.1] (JF2511).
	FIGURE 5:. Arb1 depletion delays the dissolution of heat-denatured FFL-GFP aggregates. (A) Quantitation of the percentage of cells with aggregates remaining after 30, 60, or 90 min of recovery time following heat treatment. Strains of different genotypes, all carrying the p426Met25-FFL-GFP aggregation reporter plasmid, were grown to early log phase at 30°C in selective media with galactose and raffinose as carbon sources. Cultures were then switched to selective media with glucose as carbon source for 2.5 h to deplete Arb1 and then to media lacking methionine for 1.5 h to express the FFL-GFP gene. Finally, cultures were heat treated (25 min, 42°C) and allowed to recover at 30°C for the indicated times before imaging. A minimum of 100 cells of each genotype were tabulated for each time point. Data for each strain and time point are the averages of three to six trials involving at least three transformants. Error bars are the SD of the means. ANOVA analysis with Tukey post hoc tests were used to determine the significance of observed difference in phenotype of the wild-type strain relative to strains of all other genotypes (excluding hsp104Δ) at each time point (30′, 60′, and 90′). The ARB1-d (glucose) sample was significantly different (**P < 0.01) from the wild-type strain at all three times. Other comparisons (not indicated in the figure for clarity) were nonsignificant with the exception of new1 and ARB1-d (glucose and galactose) (p < 0.01, 90′) and the arb1(ARB1) control and ARB1-d (glucose and galactose (p < 0.01, 90′). (B) Representative images for strain YDH226 under Arb1 depletion (glucose) and Arb1 expressing conditions (galactose) at indicated times following heat shock. Strains were wild type (BY4730), UASG-ARB1 (YDH226), new1Δ (JF2475), and hsp104Δ (JF2473) transformed with the pRS426 UASMET25FFL-GFP plasmid.
	FIGURE 6:. Arb1 depletion causes a defect in maintenance (propagation) of Htt-Q97 amyloids. (A) Percentage of cells maintaining Htt-Q97 –GFP aggregates in the presence or absence of candidate chaperones. Cells were grown to early log phase in selective media containing galactose (up arrow) at 30°C at which point the culture was split and galactose was washed out and replaced with selective media containing glucose (down arrow) prior to growth for another 4 h. Data for each strain are the averages of three transformants and two to three trials. Error bars are the SD of the means. Strains were arb1Δ with pDH22 (ARB1), new1Δ (JF2475), UASG-ARB1-d (arb1Δ with pDH25, YDH226) (Dong et al., 2005), and hsp104Δ (JF2473). All strains carried the p416-Htt-Q97-GFP plasmid. The significance of differences in phenotype between the wt strain and strains of other genotypes was assessed by ANOVA-Tukey HSD analysis (**p < 0.01). (B, C) Representative SDD-AGE (B) and SDS–PAGE (C) anti-GFP Western analysis of extracts prepared from haploid strains wt (BY4730), hsp104Δ (JF2473), new1 Δ (JF2475), and the arb1Δ strain YDH226 carrying the pDH25.1 Arb1 depletion plasmid. In later experiments, an arb1Δ (pARB1) strain was also included (not shown) as it proved to be a better control than the galactose grown pDH25.1, which expresses reduced levels of Arb1 due to protein destabilization (Dong et al., 2005) (Figure 4 and Supplemental Figure S4B). Three transformants were analyzed in each experiment. Approximately equal loading of extracts across lanes was evaluated by quantitation of the SDS–PAGE gel following REVERT (LI-COR) staining. In the SDD-AGE experiment, wild-type extracts were loaded at 0.5× so that the signal was more even across the blot. The difference in loading was accounted for in the analysis. (D) Aggregate load was calculated as the percentage of aggregated GFP signal over the total signal (SDS–PAGE + SDD-AGE). Significance was evaluated by ANOVA-Tukey HSD analysis (Tukey, 1949) per experiment (three transformants) to reduce the impact of technical (extract to extract) variability and keep the focus on biological variability. The hsp104Δ was significantly different (P < 0.01) from all other strains. The wt and the arb1Δ(pARB1) control strains were significantly different (*p < 0.05) from all other strains. Differences between the new1Δ and ARB1-d strains were not significant.
	FIGURE 9:. C. elegans ABCF loss of function causes germline arrest and increased amyloid production. (A) Top, experimental scheme to assess ABCF loss of function effects on development. Bottom, phenotypic quantitation. (B–E) Wild-type (B, D) or abcf-2(ok2388) (C, E) adult germlines exposed to control (B, C) or abcf-1 (D, E) RNAi and stained for amyloid oligomers (A11, green) and DNA (DAPI, blue). Frequencies of depicted phenotypes are as follows: (B) 100% n > 100; (C) 100% n = 20; (D) 100% n = 30; (E) 71% (n = 17) of germlines showed expansion of A11-positive structures into the distal germline and 76% (n = 17) showed enlarged or fused oocytes. Arrowheads denote A11 puncta. Arrows in E denote expanded A11 puncta compared with the localization in abcf-1 single loss of function animals (arrowheads in D and E). EV, empty RNAi vector. Scale bar, 50 µm.

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