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ALS/FTD Mutation-Induced Phase Transition of FUS Liquid Droplets and Reversible Hydrogels into Irreversible Hydrogels Impairs RNP Granule Function.

Murakami T, Qamar S, Lin JQ, Schierle GS, Rees E, Miyashita A, Costa AR, Dodd RB, Chan FT, Michel CH, Kronenberg-Versteeg D, Li Y, Yang SP, Wakutani Y, Meadows W, Ferry RR, Dong L, Tartaglia GG, Favrin G, Lin WL, Dickson DW, Zhen M, Ron D, Schmitt-Ulms G, Fraser PE, Shneider NA, Holt C, Vendruscolo M, Kaminski CF, St George-Hyslop P - Neuron (2015)

Bottom Line: One consequence is impairment of new protein synthesis by cytoplasmic RNP granules in axon terminals, where RNP granules regulate local RNA metabolism and translation.Nuclear FUS granules may be similarly affected.Inhibiting formation of these fibrillar hydrogel assemblies mitigates neurotoxicity and suggests a potential therapeutic strategy that may also be applicable to ALS/FTD associated with mutations in other RNA binding proteins.

View Article: PubMed Central - PubMed

Affiliation: Tanz Centre for Research in Neurodegenerative Diseases, and Departments of Medicine, Medical Biophysics and Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Ontario M5S 3H2, Canada.

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STAU-1, SMN, and TIAR-1 but Not hnRNP1 Colocalize with Mutant FUS in Cytoplasmic RNP GranulesSTAU-1, SMN, and TIAR-1 (red) colocalized with pathological intraneuronal cytoplasmic and axonal assemblies of mutant full-length FUS501, wild-type FUC-LC domain and mutant FUS(LC) domain (green) but did not colocalize with nuclear FUS(WT) (green). ∗∗∗p < 0.001. Scale bars, 2.0 μm. Additional data are shown in Figures S3B–S3D. STAU-1 colocalization: FUS(WT) = 6.0% ± 3.1%; FUS501 = 72.0 ± 5.3%; FUS(LC) = 80.0 ± 5.2%; FUS(LC)-S96del = 95.0 ± 1.7%; FUS(LC)-G156E = 95.0 ± 2.2; n = 20 neurons; p < 0.001; SMN colocalization: (FUS(WT) = 15.0 ± 3.1%; FUS 501 = 85.0 ± 3.4%; FUS(LC) = 84.0 ± 3.1%; FUS(LC)-S96del = 89.0 ± 2.3%; FUS(LC)-G156E = 88.0 ± 2.5%; n = 20 neurons; p < 0.001). Scale bars, 2.0 μm. Error bars are SEM.
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fig3: STAU-1, SMN, and TIAR-1 but Not hnRNP1 Colocalize with Mutant FUS in Cytoplasmic RNP GranulesSTAU-1, SMN, and TIAR-1 (red) colocalized with pathological intraneuronal cytoplasmic and axonal assemblies of mutant full-length FUS501, wild-type FUC-LC domain and mutant FUS(LC) domain (green) but did not colocalize with nuclear FUS(WT) (green). ∗∗∗p < 0.001. Scale bars, 2.0 μm. Additional data are shown in Figures S3B–S3D. STAU-1 colocalization: FUS(WT) = 6.0% ± 3.1%; FUS501 = 72.0 ± 5.3%; FUS(LC) = 80.0 ± 5.2%; FUS(LC)-S96del = 95.0 ± 1.7%; FUS(LC)-G156E = 95.0 ± 2.2; n = 20 neurons; p < 0.001; SMN colocalization: (FUS(WT) = 15.0 ± 3.1%; FUS 501 = 85.0 ± 3.4%; FUS(LC) = 84.0 ± 3.1%; FUS(LC)-S96del = 89.0 ± 2.3%; FUS(LC)-G156E = 88.0 ± 2.5%; n = 20 neurons; p < 0.001). Scale bars, 2.0 μm. Error bars are SEM.

Mentions: To determine whether the rescue effect was mediated at the level of FUS granules, we co-expressed RFP-tagged STAU-1 or SMN in animals expressing various FUS cDNAs. STAU-1 and SMN strongly colocalized (≥72% ± 5.3% overlap) with cytoplasmic assemblies comprised of mutant full-length FUS or aggregation-prone FUS(LC) domain. STAU-1 and SMN did not colocalize with FUS(WT) (6.0% ± 3.1%; Figures 3D and S14; n = 20 neurons; p < 0.001).


ALS/FTD Mutation-Induced Phase Transition of FUS Liquid Droplets and Reversible Hydrogels into Irreversible Hydrogels Impairs RNP Granule Function.

Murakami T, Qamar S, Lin JQ, Schierle GS, Rees E, Miyashita A, Costa AR, Dodd RB, Chan FT, Michel CH, Kronenberg-Versteeg D, Li Y, Yang SP, Wakutani Y, Meadows W, Ferry RR, Dong L, Tartaglia GG, Favrin G, Lin WL, Dickson DW, Zhen M, Ron D, Schmitt-Ulms G, Fraser PE, Shneider NA, Holt C, Vendruscolo M, Kaminski CF, St George-Hyslop P - Neuron (2015)

STAU-1, SMN, and TIAR-1 but Not hnRNP1 Colocalize with Mutant FUS in Cytoplasmic RNP GranulesSTAU-1, SMN, and TIAR-1 (red) colocalized with pathological intraneuronal cytoplasmic and axonal assemblies of mutant full-length FUS501, wild-type FUC-LC domain and mutant FUS(LC) domain (green) but did not colocalize with nuclear FUS(WT) (green). ∗∗∗p < 0.001. Scale bars, 2.0 μm. Additional data are shown in Figures S3B–S3D. STAU-1 colocalization: FUS(WT) = 6.0% ± 3.1%; FUS501 = 72.0 ± 5.3%; FUS(LC) = 80.0 ± 5.2%; FUS(LC)-S96del = 95.0 ± 1.7%; FUS(LC)-G156E = 95.0 ± 2.2; n = 20 neurons; p < 0.001; SMN colocalization: (FUS(WT) = 15.0 ± 3.1%; FUS 501 = 85.0 ± 3.4%; FUS(LC) = 84.0 ± 3.1%; FUS(LC)-S96del = 89.0 ± 2.3%; FUS(LC)-G156E = 88.0 ± 2.5%; n = 20 neurons; p < 0.001). Scale bars, 2.0 μm. Error bars are SEM.
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fig3: STAU-1, SMN, and TIAR-1 but Not hnRNP1 Colocalize with Mutant FUS in Cytoplasmic RNP GranulesSTAU-1, SMN, and TIAR-1 (red) colocalized with pathological intraneuronal cytoplasmic and axonal assemblies of mutant full-length FUS501, wild-type FUC-LC domain and mutant FUS(LC) domain (green) but did not colocalize with nuclear FUS(WT) (green). ∗∗∗p < 0.001. Scale bars, 2.0 μm. Additional data are shown in Figures S3B–S3D. STAU-1 colocalization: FUS(WT) = 6.0% ± 3.1%; FUS501 = 72.0 ± 5.3%; FUS(LC) = 80.0 ± 5.2%; FUS(LC)-S96del = 95.0 ± 1.7%; FUS(LC)-G156E = 95.0 ± 2.2; n = 20 neurons; p < 0.001; SMN colocalization: (FUS(WT) = 15.0 ± 3.1%; FUS 501 = 85.0 ± 3.4%; FUS(LC) = 84.0 ± 3.1%; FUS(LC)-S96del = 89.0 ± 2.3%; FUS(LC)-G156E = 88.0 ± 2.5%; n = 20 neurons; p < 0.001). Scale bars, 2.0 μm. Error bars are SEM.
Mentions: To determine whether the rescue effect was mediated at the level of FUS granules, we co-expressed RFP-tagged STAU-1 or SMN in animals expressing various FUS cDNAs. STAU-1 and SMN strongly colocalized (≥72% ± 5.3% overlap) with cytoplasmic assemblies comprised of mutant full-length FUS or aggregation-prone FUS(LC) domain. STAU-1 and SMN did not colocalize with FUS(WT) (6.0% ± 3.1%; Figures 3D and S14; n = 20 neurons; p < 0.001).

Bottom Line: One consequence is impairment of new protein synthesis by cytoplasmic RNP granules in axon terminals, where RNP granules regulate local RNA metabolism and translation.Nuclear FUS granules may be similarly affected.Inhibiting formation of these fibrillar hydrogel assemblies mitigates neurotoxicity and suggests a potential therapeutic strategy that may also be applicable to ALS/FTD associated with mutations in other RNA binding proteins.

View Article: PubMed Central - PubMed

Affiliation: Tanz Centre for Research in Neurodegenerative Diseases, and Departments of Medicine, Medical Biophysics and Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Ontario M5S 3H2, Canada.

Show MeSH
Related in: MedlinePlus