Misfolded protein toxicity and failure of protein quality control underlie neurodegenerative diseases including amyotrophic lateral sclerosis and frontotemporal dementia. Here, we identified Lethal(3)malignant brain tumor-like protein 1 (L3MBTL1) as a key regulator of protein quality control, the loss of which protected against the proteotoxicity of mutant Cu/Zn superoxide dismutase or C9orf72 dipeptide repeat proteins. L3MBTL1 acts by regulating p53-dependent quality control systems that degrade misfolded proteins. SET domain-containing protein 8, an L3MBTL1-associated p53-binding protein, also regulated clearance of misfolded proteins and was increased by proteotoxicity-associated stresses in mammalian cells. Both L3MBTL1 and SET domain-containing protein 8 were upregulated in the central nervous systems of mouse models of amyotrophic lateral sclerosis and human patients with amyotrophic lateral sclerosis/frontotemporal dementia. The role of L3MBTL1 in protein quality control is conserved from Caenorhabditis elegans to mammalian neurons. These results reveal a protein quality-control pathway that operates in both normal stress response and proteotoxicity-associated neurodegenerative diseases.
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This work was supported by grants from the NIH (nos. NS074324, NS089616 and NS110098), the Packard Center for ALS Research at Johns Hopkins, the Muscular Dystrophy Association, the ALS Association and the Maryland Stem Cell Research Fund (to J.W.). R.G.K. and J. M.-P. were supported by grants from the NIH (nos. NS096746 and NS093439) and the Les Turner ALS Center at Northwestern. We thank H.-Y. Hwang for assisting in C. elegans genome deep sequencing and data analysis, C. Holmberg of the University of Helsinki for the Dendra2 C. elegans strain, V. Culotta of Johns Hopkins University for the C. elegans SOD1 antibody, A. Isaacs of University College London for the proline-arginine repeat plasmid template and members of the Wang laboratory for discussion.
The authors declare no competing interests.
Journal peer review information Nature Neuroscience thanks Hande Ozdinler and the other anonymous reviewer(s) for their contribution to the peer review of this work.
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Integrated supplementary information
Supplementary Figure 1 Characterization of the lin-61 suppressor that ameliorates the locomotion defects in the C. elegans model of SOD1-associated ALS.
(a) Quantitative RT-PCR analysis of the mRNA expression levels of the SOD1G85R transgene in the presence of the loss-of-function mutation lin-61(n3809) as compared with the control background (WT) (n = 3; * P = 0.029). (b) A schematic graph that depicts the different folding states of proteins in relation to the solubility assay based on detergent extraction and centrifugation. The soluble fraction includes native proteins and the misfolded monomers and oligomers, while the insoluble fraction contains large protein aggregates. (c) Representative images showing the SOD1G85R-YFP protein aggregates in the WT or the lin-61(n3809) mutant background. The Iin-61(n3809) mutant worms show a marked decrease in protein aggregation. SOD1G85R-YFP is expressed in neurons. The head and nerve ring regions are shown. Scale bar: 5 μm. (d) Representative western blots of the SOD1G85R-YFP protein in the WT and lin-61(n3809) mutant worms (top). Quantification of SOD1G85R protein and mRNA levels (bottom). (n = 5 for proteins, *** P = 0.0005; n = 3 for mRNAs, P = 0.9862). (e) Western blots of C. elegans SOD-1 (C.e.SOD-1) in the WT (N2) and lin-61(n3809) C. elegans, showing no change in the level of the endogenous SOD-1 (top). Quantification of C. elegans SOD-1 (C.e.SOD-1) protein levels (bottom; n = 3; P = 0.3543). (f) Western blots of human wild-type SOD1 (SOD1WT) expressed in neurons of the N2 and lin-61(n3809) C. elegans (left). Quantification of human wild-type SOD1 (SOD1WT) protein level (right; n = 3; P = 0.8812). (g) Western blots of ploy-glutamine repeat (polyQ67-YFP) expressed in neurons of the N2 and lin-61(n3809) C. elegans (left). Quantification of polyQ67-YFP protein levels (right; n = 3; P = 0.5301). (h) Molecular phylogenetic analysis of L3MBTL1-related proteins. The evolutionary history was inferred by using the Maximum Likelihood method based on the JTT matrix-based model. Initial tree(s) for the heuristic search were obtained automatically by applying Neighbor-Join and BioNJ algorithms to a matrix of pairwise distances estimated using a JTT model, and then selecting the topology with superior log likelihood value. The tree is drawn to scale, with branch lengths measured in the number of substitutions per site (next to the branches). The analysis involved 5 amino acid sequences. All positions containing gaps and missing data were eliminated. There were a total of 619 positions in the final dataset. Evolutionary analyses were conducted in MEGA7. Error bars represent ± SEM.
Supplementary Figure 2 UbG76V-Dendra2 fluorescence chase experiments to determine the rate of protein degradation in lin-61 mutant suppressor C. elegans.
Representative fluorescence images of live C. elegans before and after conversion of the green Dendra2 (Green) into photo-switched red Dendra2 (Red). Scale bar: 100 μm.
(a) Representative western blots of SOD1 in total cell lysates after reduction of L3MBTL1 (left). Quantification of the WT and G85R mutant SOD1 western blots (right; n = 5, P(WT) = 0.1388, ** P(G85R) = 0.0038). (b) Representative western blots analyses of supernatants from HEK293 cells treated with non-targeting (CTRL), SETD8, or L3MBTL1 shRNAs. Unlike the misfolded SOD1 mutant G85R, the levels of wild-type SOD1 protein were not altered by the reduction of SETD8 or L3MBTL1 in the cells (top). Quantification of the SOD1 western blots (bottom; n = 3, SOD1WT: P = 0.46 (CTRL vs. SETD8), P = 0.80 (CTRL vs. L3MBTL1); SOD1G85R: * P = 0.024 (CTRL vs. SETD8)). (c) Co-immunoprecipitation analysis of Flag-tagged L3MBTL1 and endogenous p53 in HEK293 cells (left). A methyllysine-binding mutation, D355A, disrupts the interaction between L3MBTL1 and p53. Quantification of the co-IP western blots (right; n = 4; * P = 0.0114, *** P = 0.0009). (d) Western blots of cell lysates after treatments with non-targeting (CTRL) or L3MBTL1 shRNAs. Reduction of L3MBTL1 did not change the level of Flag-tagged polyQ82 proteins in both fractions from HEK293 cells (left). Quantification of the Flag-tagged polyQ82 western blots (right; n = 4, P(S) = 0.8355, P(P) = 0.9297). (e) Quantification of the SOD1WT protein clearance. The graph indicates the relative band intensity of SOD1WT at each chase time point in the L3MBTL1 shRNA-treated cells versus controls (bottom; n = 3, P = 0.3352). (f) Schematic representation of the proteasome degradation assay using destabilized fusion protein UbG76V-GFP as a readout. UbG76V-GFP is a reporter protein, formed by fusing a mutated uncleavable ubiquitin moiety with the N-terminus of GFP, which allow quantification of ubiquitin/proteasome-dependent proteolysis in living cells. (g) Schematic representation of the cell-based Proteasome-Glo activity assay. Cells are provided with a specific luminogenic proteasome peptide substrate, Suc-LLVY-aminoluciferin. When the substrate is cleaved by the proteasome, aminoluciferin is released and consumed by luciferase, resulting in a luminescent signal proportional to the proteasome activity in the cell. Error bars represent ± SEM.
(a) Reduction of SETD8 by shRNAs decreases the level of a SETD8 enzymatic product, H4K20me1, while not changing the total level of histone H4 protein levels. (b) Co-immunoprecipitation analysis of V5-tagged SETD8 and endogenous p53 proteins in HEK293 cells (left). Quantification of the co-IP western blots (right; n = 3; ** P = 0.0087). (c) Quantification of the endogenous SOD1WT protein half-life in the SETD8 shRNA-treated HEK293 cells. The SETD8 shRNAs didn’t alter the half-life of the endogenous WT SOD1 protein (n = 3, P = 0.8315). (d) HEK293 cells were expressed with Flag-tagged human WT or K382R (methylation mutant) p53 with or without Flag-SETD8 co-expression or MG132 treatment (20 μM, 2hr), and the steady-state levels of p53 proteins were analyzed by western blotting (top). The presence of the mutation K382R, which disrupts methyllysine-binding, decreased the levels of p53 protein as well as the co-expressed SETD8 protein. The decrease of the p53-K382R or SETD8 protein was partially rescued with the MG132 treatment. Quantification of p53 and SETD8 protein levels (n = 3; P53: * P = 0.036 (p53WT vs. p53K382R), * P = 0.0245 (p53WT vs. p53WT with SETD8), **** P<0.0001(p53WT with SETD8 vs. p53K382R with SETD8), * P = 0.0309 (p53K382R with SETD8 vs. p53K382R with SETD8 and MG132); SETD8: ** P = 0.007 (p53WT with SETD8 vs. p53K382R with SETD8), * P = 0.0103 (p53K382R with SETD8 vs. p53K382R with SETD8 and MG132)). (e) Western blots of a representative cycloheximide chase experiment to determine the half-life of p53WT or p53K382R in HEK293 cells with SETD8-GFP co-expression (left). Quantification of p53 and SETD8 clearance with p53WT or p53K382R as measured by the western blots. The graph indicates the relative band intensity of p53 or SETD8 at each chase time point (right; n = 3; P53: P = 0.0494; SETD8: P≤0.048 for each time point). (f) Western blots of cell lysates after treatment with non-targeting (CTRL), SETD8, L3MBTL1, or double shRNAs. Reduction of SETD8 decreases the level of p53 protein, an effect that can be reversed by the reduction of L3MBTL1 (left). Quantification of the p53 and SOD1G85R western blots (right; n = 3, P53: *** P = 0.0006 (CTRL vs. ShSETD8), ** P = 0.0082 (ShSETD8 vs. ShSETD8+ShL3MBTL1), SOD1G85R: * P = 0.0298 (CTRL vs. ShSETD8), *** P = 0.0006 (CTRL vs. ShL3MBTL1), ** P = 0.0056 (CTRL vs. ShSETD8+ShL3MBTL1)). Error bars represent ± SEM.
(a) Treatment with the proteasome inhibitor MG132 (20 μM for 1 h) increases the level of SETD8 protein in MEF cells. (b) Quantification of SETD8 protein levels after treatment of MG132 (n = 5; * P = 0.0256). (c) Quantification of SETD8 mRNA levels after MG132 treatment on MEF cells (n = 3; *** P<0.0001). (d) Western blot analyses of spinal cord lysates from non-transgenic, SOD1WT-YFP, presymptomatic (Pre) and symptomatic (Sym) SOD1G85R-YFP, and SOD1G93A transgenic mice show an increase in the levels of H4K20me1 (an enzymatic product of SETD8-mediated methylation) and p53, occurring in a mutant SOD1- and symptom-dependent manner. Total H4 protein levels were not changed. (e) Additional ALS patients’ spinal cords were analyzed by western blotting for the expression levels of SETD8. The control and ALS samples were run on the same gel but separated by other samples. The full blot is shown in the supplementary information. (f) Western blot analyses of SETD8 in the brain region of occipital cortex from ALS patients and healthy controls (left). Unlike spinal cords of ALS patients, in which SETD8 is up-regulated, the occipital cortex from the same patients shows no significant change in the SETD8 protein levels (right; n = 3 controls and 5 patients, P = 0.19). (g) Western blot analyses of SETD8 in the brain region of inferior parietal cortex from Alzheimer’s disease (AD) patients and healthy controls show a reduction of the SETD8 protein in AD brains (n = 4 controls and 7 patients, * P = 0.03). The control and AD samples were run on the same gel but separated by other samples. The full blot is shown in the supplementary information. Error bars represent ± SEM.
Supplementary Figure 6 L3MBTL1 is upregulated in spinal cords of mutant SOD1 mice and a subset of patients with ALS.
(a) Western blot analyses of spinal cord lysates from age-matched non-transgenic (NTg) and symptomatic SOD1G93A transgenic mice show an increase in the levels of L3MBTL1 in the mutant SOD1 animals. (b) Quantification of L3MBTL1 protein levels by western blotting (n = 3, * P = 0.0354). (c) Immunofluorescence staining analysis shows increased levels of L3MBTL1 in neurons of symptomatic SOD1G93A transgenic mice compared to age- and gender-controlled non-transgenic mice. NeuN is a neuronal marker (left). Quantification of L3MBTL1 immunofluorescence signals in spinal cord neurons from three independent sets of mice (right; n = 3, * P = 0.036). (d) Representative western blot analyses of L3MBTL1 in the spinal cords from ALS patients and healthy controls (left). Quantification of L3MBTL1 protein levels as measured in the western blots (right; n = 6 controls and 10 patients, * P = 0.031). Error bars represent ± SEM.
Representative images of Drosophila adult eyes in RNAi strains without the expression of poly(GR) or poly(PR) proteins, showing normal eye phenotypes. Scale Bar: 100 μm.
(a) Western blot analyses of HEK293 cells treated with increasing concentrations of UNC669 showed that the level of endogenous SOD1WT protein was not affected by the treatment (n = 3; n.s. = non-significant; P(0 vs. 25) = 0.2035; P(0 vs. 50) = 0.0569; P(0 vs. 100) = 0.1514). (b) Mouse embryonic stem cell-derived motor neurons were transduced with GFP-expressing viral vectors and treated with vehicle or 100 µM UNC669 for six days. Cells were then loaded with calcein AM and imaged for cell viability using fluorescence microscopy (left). Quantification of the calcein AM by using a plate reader (right; n = 5; P = 0.36). There was no change in the survival of the GFP-expressing motor neurons. Scale Bar: 300 μm. (c) Rat primary spinal cord neuronal cultures were treated with 100 µM UNC669 or vehicle (EtOH, VEH). The cells were stained with a motor neuron-specific anti-NF-H antibody SMI-32 and imaged using fluorescence microscopy (left). Quantification of the counts of surviving rat motor neurons (right; n = 12, P = 0.95). Scale Bar: 300 μm. (d) Representative images of immunofluorescence staining using an antibody that recognizes the misfolded SOD1 protein, on spinal cord sections from SOD1G93A mice treated with UNC669 or vehicle controls. Arrows point to ventral horns of lumbar spinal cords. (e) Representative images of immunofluorescence co-staining using antibodies against both misfolded SOD1 and ChAT as a motor neuron marker on spinal cord from SOD1G93A mice treated with UNC669 or vehicle controls. Error bars represent ± SEM.
Supplementary Figure 9 Schematic summary of protein quality control programs modulated by L3MBTL1 and SETD8.
L3MBTL1 negatively regulates p53 activity, the proteasomal degradation, and the turnover of misfolded proteins. Accumulation of misfolded proteins leads to accumulation/activation of SETD8, which enhances protein quality control and clearance of misfolded proteins, an effect partially mediated by L3MBTL1. Together, these regulators constitute a protein quality control pathway that senses and controls the levels of misfolded proteins and associated toxicities.
Scans of immunoblots presented in the study.
Scans of immunoblots presented in the study.
Scans of immunoblots presented in the study.
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Lu, J., Periz, G., Lu, YN. et al. L3MBTL1 regulates ALS/FTD-associated proteotoxicity and quality control. Nat Neurosci 22, 875–886 (2019). https://doi.org/10.1038/s41593-019-0384-5
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