RNA Binding Antagonizes Neurotoxic Phase Transitions of TDP-43

Mann, Jacob R.; Gleixner, Amanda M.; Mauna, Jocelyn C.; Gomes, Edward; DeChellis-Marks, Michael R.; Needham, Patrick G.; Copley, Katie E.; Hurtle, Bryan T.; Portz, Bede; Pyles, Noah J.; Guo, Lin; Calder, Christopher B.; Wills, Zachary P.; Pandey, Udai Bhan; Kofler, Julia; Brodsky, Jeffrey L.; Thathiah, Amantha; Shorter, James; Donnelly, Christopher J.

doi:10.1016/j.neuron.2019.01.048

Cited by 434 publications

(551 citation statements)

References 67 publications

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“…within the TDP43 C-terminus promotes liquid-phase separation and aggregation (90)(91)(92)(93)(94). Even so, our observations and those of others (64,65) show that sTDP43 is relatively insoluble and prone to aggregation, despite lacking the LCD.…”

Section: Discussionsupporting

confidence: 67%

“…In keeping with previous studies 65 , overexpressed sTDP43 accumulates in the cytoplasm where it often forms large, insoluble inclusions. The low-complexity domain (LCD) within the TDP43 C-terminus is essential for liquid-phase separation [87][88][89][90] , and has been heavily implicated in TDP43 aggregation. Even so, our observations and those of others 64,65 show that sTDP43 is insoluble and prone to aggregation, despite lacking the LCD.…”

Section: Discussionmentioning

confidence: 99%

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Shortened TDP43 isoforms upregulated by neuronal hyperactivity drive TDP43 pathology in ALS

Weskamp

Tank

Miguez

et al. 2019

Preprint

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Cortical hyperexcitability and mislocalization of the RNA-binding protein TDP43 are highlyconserved features in amyotrophic lateral sclerosis (ALS). Nevertheless, the relationship between these phenomena remains poorly defined. Here, we showed that hyperexcitability recapitulates TDP43 pathology by upregulating shortened (s) TDP43 splice isoforms. These truncated isoforms accumulated in the cytoplasm and formed insoluble inclusions that sequestered full-length TDP43 via preserved N-terminal interactions. Consistent with these findings, sTDP43 overexpression was toxic to mammalian neurons, suggesting neurodegeneration arising from complementary gain-and loss-of-function mechanisms. In humans and mice, sTDP43 transcripts were enriched in vulnerable motor neurons, and we observed a striking accumulation of sTDP43 within neurons and glia of ALS patients. Collectively, these studies uncover a pathogenic role for alternative TDP43 isoforms in ALS, and implicate sTDP43 as a key contributor to the susceptibility of motor neurons in this disorder.

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Section: Discussionsupporting

confidence: 67%

Section: Discussionmentioning

confidence: 99%

Shortened TDP43 isoforms upregulated by neuronal hyperactivity drive TDP43 pathology in ALS

Weskamp

Tank

Miguez

et al. 2019

Preprint

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“…RNA also appears to play an important role in the formation of these structures. Indeed, RNA itself undergoes phase transition (Jain & Vale, 2017) and has been shown to promote phase transitions of several proteins (Lin et al, 2015;Molliex et al, 2015;Zhang et al, 2015), including Tau (Zhang et al, 2017), and also to inhibit protein aggregation, most notably of Fused in Sarcoma, FUS and TDP-43 (Burke et al, 2015;Mann et al, 2019;Shelkovnikova et al, 2014). Recently, Maharana et al, showed that for several prion-like proteins, including FUS, these disparate effects can be explained by the ratio of protein to RNA; where excess of RNA promotes solubility and decreased amount of RNA induces phase-transition (Maharana et al, 2018).…”

Section: Introductionmentioning

confidence: 99%

Enzymatic degradation of RNA causes widespread protein aggregation in cell and tissue lysates

Aarum

Cabrera

Jones

et al. 2019

Preprint

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Most proteins in cell and tissue lysates are soluble. Here, we show that many of these proteins, including several that are implicated in neurodegenerative diseases, are maintained in a soluble and functional state by association with endogenous RNA, as degradation of RNA invariably leads to protein aggregation. We identify the importance of nucleic acid structure, with single-stranded pyrimidine-rich bulges or loops surrounded by doublestranded regions being particularly efficient in this role, revealing an apparent one-to-one protein-nucleic acid stoichiometry. The relationship of these findings to pathological protein aggregation is suggested by our discovery that protein aggregates isolated from brain tissue from Amyotrophic Lateral Sclerosis patients can be rendered soluble after refolding by both RNA and synthetic oligonucleotides. Together, these findings open new avenues for understanding the mechanism behind protein aggregation and shed light on how certain proteins remain soluble. KEYWORDSmotor neurone disease / protein precipitation / ribonuclease / neurofilament / phase-transition

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“…Microinjection of RNase A can induce aggregation of nuclear FUS protein in vivo, suggesting that, in this case, high levels of RNA oppose phase separation. RNA binding-defective mutants of TDP-43 display an increased propensity to phase separate in vitro and in vivo and addition of TDP-43 RNA substrates allows TDP-43 to remain soluble (Maharana et al, 2018;J. R. Mann et al, 2019).…”

Section: Introductionmentioning

confidence: 99%

RNA promotes phase separation of glycolysis enzymes into yeast G bodies in hypoxia

Fuller

Han

Freeberg

et al. 2019

Preprint

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AbstractIn hypoxic stress conditions, glycolysis enzymes assemble into singular cytoplasmic granules called glycolytic (G) bodies. Formation of G bodies in yeast is correlated with increased glucose consumption and cell survival. However, the physical properties and organizing principles that define G body formation are unclear. We demonstrate that glycolysis enzymes are non-canonical RNA binding proteins, sharing many common mRNA substrates that are also integral constituents of G bodies. Tethering a G body component, the beta subunit of the yeast phosphofructokinase, Pfk2, to nonspecific endoribonucleases reveals that RNA nucleates G body formation and subsequent maintenance of G body structural integrity. Consistent with a phase separation mechanism of G body formation, recruitment of glycolysis enzymes to G bodies relies on multivalent homotypic and heterotypic interactions. Furthermore, G bodies can fuse in live cells and are largely insensitive to 1,6-hexanediol treatment, consistent with a hydrogel-like state in its composition. Taken together, our results elucidate the biophysical nature of G bodies and demonstrate that RNA nucleates phase separation of the glycolysis machinery in response to hypoxic stress.

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RNA Binding Antagonizes Neurotoxic Phase Transitions of TDP-43

Cited by 434 publications

References 67 publications

Shortened TDP43 isoforms upregulated by neuronal hyperactivity drive TDP43 pathology in ALS

Shortened TDP43 isoforms upregulated by neuronal hyperactivity drive TDP43 pathology in ALS

Enzymatic degradation of RNA causes widespread protein aggregation in cell and tissue lysates

RNA promotes phase separation of glycolysis enzymes into yeast G bodies in hypoxia

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