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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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Neurotoxicity of Mutant FUS in C. elegans and Reduced New Protein Synthesis in Xenopus Neurons Are Unlikely to be Due to Activation of the UPR due to Accumulation of Misfolded FUS(A) In vivo stress granule density measured by counting pab-l-positive granules in C. elegans under basal conditions and after heat shock were not different between control (empty vector); FUS(WT) and mutant FUS animals, indicating that mutant FUS animals were not under greater unfolded protein stress.(B) Thapsigargin treatment induced UPR and reduced new protein synthesis in Xenopus neurons expressing FUS(WT). PERK1 inhibitors rescued reduced protein synthesis in thapsigargin-treated neurons expressing FUS(WT), but not mutant FUS-expressing neurons.Error bars are SEM.
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fig8: Neurotoxicity of Mutant FUS in C. elegans and Reduced New Protein Synthesis in Xenopus Neurons Are Unlikely to be Due to Activation of the UPR due to Accumulation of Misfolded FUS(A) In vivo stress granule density measured by counting pab-l-positive granules in C. elegans under basal conditions and after heat shock were not different between control (empty vector); FUS(WT) and mutant FUS animals, indicating that mutant FUS animals were not under greater unfolded protein stress.(B) Thapsigargin treatment induced UPR and reduced new protein synthesis in Xenopus neurons expressing FUS(WT). PERK1 inhibitors rescued reduced protein synthesis in thapsigargin-treated neurons expressing FUS(WT), but not mutant FUS-expressing neurons.Error bars are SEM.

Mentions: We have previously noted that C. elegans expressing either full-length wild-type FUS or full-length mutant FUS had very few intra-cytoplasmic stress granules (zero to two per neuron; p = N.S.) (Murakami et al., 2012). However, animals expressing FUS (WT) and animals expressing mutant FUS are all clearly capable of mounting a vigorous stress response after heat shock, displaying abundant stress granules (five to six granules/cell) (Figure 8, left panel; p = N.S.). These in vivo observations suggest that (1) animals expressing mutant or wild-type FUS are capable of mounting a stress response and (2) mutant-expressing animals are not more stressed by accumulation of misfolded mutant FUS than are animals expressing wild-type FUS.


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)

Neurotoxicity of Mutant FUS in C. elegans and Reduced New Protein Synthesis in Xenopus Neurons Are Unlikely to be Due to Activation of the UPR due to Accumulation of Misfolded FUS(A) In vivo stress granule density measured by counting pab-l-positive granules in C. elegans under basal conditions and after heat shock were not different between control (empty vector); FUS(WT) and mutant FUS animals, indicating that mutant FUS animals were not under greater unfolded protein stress.(B) Thapsigargin treatment induced UPR and reduced new protein synthesis in Xenopus neurons expressing FUS(WT). PERK1 inhibitors rescued reduced protein synthesis in thapsigargin-treated neurons expressing FUS(WT), but not mutant FUS-expressing neurons.Error bars are SEM.
© Copyright Policy - CC BY
Related In: Results  -  Collection

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getmorefigures.php?uid=PMC4660210&req=5

fig8: Neurotoxicity of Mutant FUS in C. elegans and Reduced New Protein Synthesis in Xenopus Neurons Are Unlikely to be Due to Activation of the UPR due to Accumulation of Misfolded FUS(A) In vivo stress granule density measured by counting pab-l-positive granules in C. elegans under basal conditions and after heat shock were not different between control (empty vector); FUS(WT) and mutant FUS animals, indicating that mutant FUS animals were not under greater unfolded protein stress.(B) Thapsigargin treatment induced UPR and reduced new protein synthesis in Xenopus neurons expressing FUS(WT). PERK1 inhibitors rescued reduced protein synthesis in thapsigargin-treated neurons expressing FUS(WT), but not mutant FUS-expressing neurons.Error bars are SEM.
Mentions: We have previously noted that C. elegans expressing either full-length wild-type FUS or full-length mutant FUS had very few intra-cytoplasmic stress granules (zero to two per neuron; p = N.S.) (Murakami et al., 2012). However, animals expressing FUS (WT) and animals expressing mutant FUS are all clearly capable of mounting a vigorous stress response after heat shock, displaying abundant stress granules (five to six granules/cell) (Figure 8, left panel; p = N.S.). These in vivo observations suggest that (1) animals expressing mutant or wild-type FUS are capable of mounting a stress response and (2) mutant-expressing animals are not more stressed by accumulation of misfolded mutant FUS than are animals expressing wild-type FUS.

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