RNA-binding proteins with prion-like domains in ALS and FTLD-U

Gitler, Aaron D.; Shorter, James

doi:10.4161/pri.5.3.17230

Cited by 144 publications

(123 citation statements)

References 146 publications

(137 reference statements)

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“…The availability of these algorithms led to the discovery of many prion-like sequences in higher eukaryotes (13). A substantial fraction of these prion-like proteins has now been implicated in protein-misfolding diseases (13)(14)(15). To further characterize the aggregation potential of the D. discoideum proteome, we used one such algorithm, based on a hidden Markov model.…”

Section: Resultsmentioning

confidence: 99%

“…Protein domains with such distinctive compositions are referred to as prion-like. Interestingly, prion-like sequence stretches are also present in aggregationprone proteins that have been associated with human neurodegenerative diseases, such as amyotrophic lateral sclerosis or frontotemporal lobar degeneration (13)(14)(15). Moreover, homopolymeric glutamine sequences and, in particular, their expanded variants have also been shown to cause neurodegenerative diseases, such as Huntington's disease or ataxia (16)(17)(18).…”

Section: Significancementioning

confidence: 99%

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Dictyostelium discoideum has a highly Q/N-rich proteome and shows an unusual resilience to protein aggregation

Malinovska

Palm

Gibson

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

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Many protein-misfolding diseases are caused by proteins carrying prion-like domains. These proteins show sequence similarity to yeast prion proteins, which can interconvert between an intrinsically disordered and an aggregated prion state. The natural presence of prions in yeast has provided important insight into disease mechanisms and cellular proteostasis. However, little is known about prions in other organisms, and it is not yet clear whether the findings in yeast can be generalized. Using bioinformatics tools, we show that Dictyostelium discoideum has the highest content of prion-like proteins of all organisms investigated to date, suggesting that its proteome has a high overall aggregation propensity. To study mechanisms regulating these proteins, we analyze the behavior of several well-characterized prion-like proteins, such as an expanded version of human huntingtin exon 1 (Q103) and the prion domain of the yeast prion protein Sup35 (NM), in D. discoideum. We find that these proteins remain soluble and are innocuous to D. discoideum, in contrast to other organisms, where they form cytotoxic cytosolic aggregates. However, when exposed to conditions that compromise molecular chaperones, these proteins aggregate and become cytotoxic. We show that the disaggregase Hsp101, a molecular chaperone of the Hsp100 family, dissolves heat-induced aggregates and promotes thermotolerance. Furthermore, prion-like proteins accumulate in the nucleus, where they are targeted by the ubiquitin-proteasome system. Our data suggest that D. discoideum has undergone specific adaptations that increase the proteostatic capacity of this organism and allow for an efficient regulation of its prion-like proteome. molecular chaperones | proteostasis | Dictyostelium discoideum | protein aggregation | prion

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Section: Resultsmentioning

confidence: 99%

Section: Significancementioning

confidence: 99%

Dictyostelium discoideum has a highly Q/N-rich proteome and shows an unusual resilience to protein aggregation

Malinovska

Palm

Gibson

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

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“…The FUS LC has garnered particular attention because its polar‐rich sequence resembles so‐called prion domains that form self‐propagating amyloid aggregates in yeast cells (Gitler & Shorter, 2011; Ju et al , 2011; Kryndushkin et al , 2011; Sun et al , 2011). Yeast prion domains contain a paucity of hydrophobic and charged residues, but are rich in polar residues, especially glutamine and asparagine (Ross & Toombs, 2010).…”

Section: Introductionmentioning

confidence: 99%

Phosphorylation of the FUS low‐complexity domain disrupts phase separation, aggregation, and toxicity

et al. 2017

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Neuronal inclusions of aggregated RNA‐binding protein fused in sarcoma (FUS) are hallmarks of ALS and frontotemporal dementia subtypes. Intriguingly, FUS's nearly uncharged, aggregation‐prone, yeast prion‐like, low sequence‐complexity domain (LC) is known to be targeted for phosphorylation. Here we map in vitro and in‐cell phosphorylation sites across FUS LC. We show that both phosphorylation and phosphomimetic variants reduce its aggregation‐prone/prion‐like character, disrupting FUS phase separation in the presence of RNA or salt and reducing FUS propensity to aggregate. Nuclear magnetic resonance spectroscopy demonstrates the intrinsically disordered structure of FUS LC is preserved after phosphorylation; however, transient domain collapse and self‐interaction are reduced by phosphomimetics. Moreover, we show that phosphomimetic FUS reduces aggregation in human and yeast cell models, and can ameliorate FUS‐associated cytotoxicity. Hence, post‐translational modification may be a mechanism by which cells control physiological assembly and prevent pathological protein aggregation, suggesting a potential treatment pathway amenable to pharmacologic modulation.

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“…In addition, FUS fusion proteins have been identified in a variety of human cancers including acute myeloid leukemia, angiomatoid fibrous histiocytoma, and fibromyxoid sarcoma (29). FUS is composed of N-terminal Gln/Gly/Ser/Tyr-rich and Gly-rich regions that comprise a prion-like domain (PLD) (30), an RNA recognition motif (RRM), arginine/glycine-rich (RGG) domains, and a C-terminal zinc finger domain (ZNF) (see Fig. 2A) (31).…”

mentioning

confidence: 99%

The RNA-binding Protein Fused in Sarcoma (FUS) Functions Downstream of Poly(ADP-ribose) Polymerase (PARP) in Response to DNA Damage

Mastrocola¹,

Kim²,

Trinh³

et al. 2013

Journal of Biological Chemistry

229

249

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Background: FUS has been implicated in the DNA damage response; however, the mechanisms are unknown. Results: FUS recruitment to DNA lesions is PARP-dependent. Depletion of FUS disrupts DNA repair. Conclusion: FUS functions downstream of PARP and promotes double-strand break repair. Significance: This work identifies FUS as a novel factor at DNA lesions and furthers our understanding of RNA-binding proteins in maintaining genomic stability.

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RNA-binding proteins with prion-like domains in ALS and FTLD-U

Cited by 144 publications

References 146 publications

Dictyostelium discoideum has a highly Q/N-rich proteome and shows an unusual resilience to protein aggregation

Dictyostelium discoideum has a highly Q/N-rich proteome and shows an unusual resilience to protein aggregation

Phosphorylation of the FUS low‐complexity domain disrupts phase separation, aggregation, and toxicity

The RNA-binding Protein Fused in Sarcoma (FUS) Functions Downstream of Poly(ADP-ribose) Polymerase (PARP) in Response to DNA Damage

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