Abstract
Recent advances suggest that the response of RNA metabolism to stress has an important role in the pathophysiology of neurodegenerative diseases, particularly amyotrophic lateral sclerosis, frontotemporal dementias and Alzheimer disease. RNA-binding proteins (RBPs) control the utilization of mRNA during stress, in part through the formation of membraneless organelles termed stress granules (SGs). These structures form through a process of liquid–liquid phase separation. Multiple biochemical pathways regulate SG biology. The major signalling pathways regulating SG formation include the mammalian target of rapamycin (mTOR)–eukaryotic translation initiation factor 4F (eIF4F) and eIF2α pathways, whereas the pathways regulating SG dispersion and removal are mediated by valosin-containing protein and the autolysosomal cascade. Post-translational modifications of RBPs also strongly contribute to the regulation of SGs. Evidence indicates that SGs are supposed to be transient structures, but the chronic stresses associated with ageing lead to chronic, persistent SGs that appear to act as a nidus for the aggregation of disease-related proteins. We suggest a model describing how intrinsic vulnerabilities within the cellular RNA metabolism might lead to the pathological aggregation of RBPs when SGs become persistent. This process might accelerate the pathophysiology of many neurodegenerative diseases and myopathies, and it suggests new targets for disease intervention.
This is a preview of subscription content, access via your institution
Access options
Access Nature and 54 other Nature Portfolio journals
Get Nature+, our best-value online-access subscription
$29.99 / 30 days
cancel any time
Subscribe to this journal
Receive 12 print issues and online access
$189.00 per year
only $15.75 per issue
Buy this article
- Purchase on Springer Link
- Instant access to full article PDF
Prices may be subject to local taxes which are calculated during checkout
Similar content being viewed by others
References
Nott, T. J. et al. Phase transition of a disordered nuage protein generates environmentally responsive membraneless organelles. Mol. Cell 57, 936–947 (2015).
Boeynaems, S. et al. Protein phase separation: a new phase in cell biology. Trends Cell Biol. 28, 420–435 (2018).
Taylor, J. P., Brown, R. H., Jr. & Cleveland, D. W. Decoding ALS: from genes to mechanism. Nature 539, 197–206 (2016).
Irwin, D. J. et al. Frontotemporal lobar degeneration: defining phenotypic diversity through personalized medicine. Acta Neuropathol. 129, 469–491 (2015).
Kim, H. J. et al. Therapeutic modulation of eIF2α phosphorylation rescues TDP-43 toxicity in amyotrophic lateral sclerosis disease models. Nat. Genet. 46, 152–160 (2014).
Radford, H., Moreno, J. A., Verity, N., Halliday, M. & Mallucci, G. R. PERK inhibition prevents tau-mediated neurodegeneration in a mouse model of frontotemporal dementia. Acta Neuropathol. 130, 633–642 (2015).
Chia, R., Chio, A. & Traynor, B. J. Novel genes associated with amyotrophic lateral sclerosis: diagnostic and clinical implications. Lancet Neurol. 17, 94–102 (2018).
Jack, C. R., Jr. et al. NIA-AA research framework: toward a biological definition of alzheimer’s disease. Alzheimers Dement. 14, 535–562 (2018).
Jin, M. et al. Soluble amyloid beta-protein dimers isolated from Alzheimer cortex directly induce Tau hyperphosphorylation and neuritic degeneration. Proc. Natl Acad. Sci. USA 108, 5819–5824 (2011).
Bang, J., Spina, S. & Miller, B. L. Frontotemporal dementia. Lancet 386, 1672–1682 (2015).
Lin, Y., Protter, D. S., Rosen, M. K. & Parker, R. Formation and maturation of phase-separated liquid droplets by RNA-binding proteins. Mol. Cell 60, 208–219 (2015).
Liu-Yesucevitz, L. et al. Local RNA translation at the synapse and in disease. J. Neurosci. 31, 16086–16093 (2011).
Parker, R. & Sheth, U. P bodies and the control of mRNA translation and degradation. Mol. Cell 25, 635–646 (2007).
Mao, Y. S., Zhang, B. & Spector, D. L. Biogenesis and function of nuclear bodies. Trends Genet. 27, 295–306 (2011).
Shpargel, K. B. & Matera, A. G. Gemin proteins are required for efficient assembly of Sm-class ribonucleoproteins. Proc. Natl Acad. Sci. USA 102, 17372–17377 (2005).
Zhang, H. et al. Multiprotein complexes of the survival of motor neuron protein SMN with Gemins traffic to neuronal processes and growth cones of motor neurons. J. Neurosci. 26, 8622–8632 (2006).
DeJesus-Hernandez, M. et al. Expanded GGGGCC hexanucleotide repeat in noncoding region of C9ORF72 causes chromosome 9p-linked FTD and ALS. Neuron 72, 245–256 (2011).
Renton, A. E. et al. A hexanucleotide repeat expansion in C9ORF72 is the cause of chromosome 9p21-linked ALS-FTD. Neuron 72, 257–268 (2011).
Jain, A. & Vale, R. D. RNA phase transitions in repeat expansion disorders. Nature 546, 243–247 (2017).
Fay, M. M., Anderson, P. J. & Ivanov, P. ALS/FTD-associated C9ORF72 repeat RNA promotes phase transitions in vitro and in cells. Cell Rep. 21, 3573–3584 (2017).
Van Treeck, B. et al. RNA self-assembly contributes to stress granule formation and defining the stress granule transcriptome. Proc. Natl Acad. Sci. USA 115, 2734–2739 (2018).
Maharana, S. et al. RNA buffers the phase separation behavior of prion-like RNA binding proteins. Science 360, 918–921 (2018). This study elegantly shows the important role that RNA plays in regulating the phase separation dynamics of membraneless organelles.
Guo, L. et al. Nuclear-import receptors reverse aberrant phase transitions of RNA-binding proteins with prion-like domains. Cell 173, 677–692.e620 (2018). This paper demonstrates that nuclear import receptors can act as disaggregates, thereby providing a novel mechanism for regulating SGs and identifying a functional link between the nuclear transport machinery and disease pathology.
Hofweber, M. et al. Phase separation of FUS is suppressed by its nuclear import receptor and arginine methylation. Cell 173, 706–719.e713 (2018).
Qamar, S. et al. FUS phase separation is modulated by a molecular chaperone and methylation of arginine cation–pi interactions. Cell 173, 720–734.e715 (2018).
Liu-Yesucevitz, L. et al. Tar DNA binding protein-43 (TDP-43) associates with stress granules: analysis of cultured cells and pathological brain tissue. PLOS ONE 5, e13250 (2010). This report shows that TDP43 associates with SGs and also provides immunohistochemical evidence that TDP43 pathology associates with SG markers in ALS brain tissue.
Gupta, N. et al. Stress granule-associated protein G3BP2 regulates breast tumor initiation. Proc. Natl Acad. Sci. USA 114, 1033–1038 (2017).
Valentin-Vega, Y. A. et al. Cancer-associated DDX3X mutations drive stress granule assembly and impair global translation. Sci. Rep. 6, 25996 (2016).
Anderson, P., Kedersha, N. & Ivanov, P. Stress granules, P-bodies and cancer. Biochim. Biophys. Acta 1849, 861–870 (2015).
Kedersha, N. et al. Dynamic shuttling of TIA-1 accompanies the recruitment of mRNA to mammalian stress granules. J. Cell Biol. 151, 1257–1268 (2000).
Kedersha, N. L., Gupta, M., Li, W., Miller, I. & Anderson, P. RNA-binding proteins TIA-1 and TIAR link the phosphorylation of eIF-2α to the assembly of mammalian stress granules. J. Cell Biol. 147, 1431–1442 (1999).
Anderson, P. & Kedersha, N. Stress granules: the Tao of RNA triage. Trends Biochem. Sci. 33, 141–150 (2008).
Kedersha, N. et al. Evidence that ternary complex (eIF2–GTP–tRNAi Met)-deficient preinitiation complexes are core constituents of mammalian stress granules. Mol. Biol. Cell 13, 195–210 (2002).
Markmiller, S. et al. Context-dependent and disease-specific diversity in protein interactions within stress granules. Cell 172, 590–604.e513 (2018). This paper provides a comprehensive characterization of SG proteomes in cells and also highlights the compositional differences among different types of SGs.
Lastres-Becker, I. et al. Mammalian ataxin-2 modulates translation control at the pre-initiation complex via PI3K/mTOR and is induced by starvation. Biochim. Biophys. Acta 1862, 1558–1569 (2016).
Kedersha, N. et al. G3BP–caprin1–USP10 complexes mediate stress granule condensation and associate with 40S subunits. J. Cell Biol. 212, 845–860 (2016).
Ohn, T., Kedersha, N., Hickman, T., Tisdale, S. & Anderson, P. A functional RNAi screen links O-GlcNAc modification of ribosomal proteins to stress granule and processing body assembly. Nat. Cell Biol. 10, 1224–1231 (2008).
Jain, S. et al. ATPase-modulated stress granules contain a diverse proteome and substructure. Cell 164, 487–498 (2016).
Wheeler, J. R., Jain, S., Khong, A. & Parker, R. Isolation of yeast and mammalian stress granule cores. Methods 126, 12–17 (2017).
Wheeler, J. R., Matheny, T., Jain, S., Abrisch, R. & Parker, R. Distinct stages in stress granule assembly and disassembly. eLife 5, e18413 (2016).
Antar, L. N., Afroz, R., Dictenberg, J. B., Carroll, R. C. & Bassell, G. J. Metabotropic glutamate receptor activation regulates fragile X mental retardation protein and FMR1 mRNA localization differentially in dendrites and at synapses. J. Neurosci. 24, 2648–2655 (2004).
Jackson, R. J., Hellen, C. U. & Pestova, T. V. The mechanism of eukaryotic translation initiation and principles of its regulation. Nat. Rev. Mol. Cell Biol. 11, 113–127 (2010). This review provides an outstanding and detailed overview of the machinery carrying out translational initiation and the pathways of translational regulation.
Fujimura, K., Sasaki, A. T. & Anderson, P. Selenite targets eIF4E-binding protein-1 to inhibit translation initiation and induce the assembly of non-canonical stress granules. Nucleic Acids Res. 40, 8099–8110 (2012).
Emara, M. M. et al. Hydrogen peroxide induces stress granule formation independent of eIF2α phosphorylation. Biochem. Biophys. Res. Commun. 423, 763–769 (2012).
Szaflarski, W. et al. Vinca alkaloid drugs promote stress-induced translational repression and stress granule formation. Oncotarget 7, 30307–30322 (2016).
Saxton, R. A. & Sabatini, D. M. mTOR signaling in growth, metabolism, and disease. Cell 168, 960–976 (2017).
Thoreen, C. C. et al. A unifying model for mTORC1-mediated regulation of mRNA translation. Nature 485, 109–113 (2012).
Frydryskova, K. et al. Distinct recruitment of human eIF4E isoforms to processing bodies and stress granules. BMC Mol. Biol. 17, 21 (2016).
Wek, R. C. Role of eif2α kinases in translational control and adaptation to cellular stress. Cold Spring Harb. Perspect. Biol. 10, a032870 (2018).
Wek, S. A., Zhu, S. & Wek, R. C. The histidyl-tRNA synthetase-related sequence in the eIF-2α protein kinase GCN2 interacts with tRNA and is required for activation in response to starvation for different amino acids. Mol. Cell Biol. 15, 4497–4506 (1995).
Harding, H. P., Zhang, Y., Bertolotti, A., Zeng, H. & Ron, D. Perk is essential for translational regulation and cell survival during the unfolded protein response. Mol. Cell 5, 897–904 (2000).
Srivastava, S. P., Kumar, K. U. & Kaufman, R. J. Phosphorylation of eukaryotic translation initiation factor 2 mediates apoptosis in response to activation of the double-stranded RNA-dependent protein kinase. J. Biol. Chem. 273, 2416–2423 (1998).
McEwen, E. et al. Heme-regulated inhibitor kinase-mediated phosphorylation of eukaryotic translation initiation factor 2 inhibits translation, induces stress granule formation, and mediates survival upon arsenite exposure. J. Biol. Chem. 280, 16925–16933 (2005).
Sudhakar, A. et al. Phosphorylation of serine 51 in initiation factor 2α (eIF2α) promotes complex formation between eIF2α(P) and eIF2B and causes inhibition in the guanine nucleotide exchange activity of eIF2B. Biochemistry 39, 12929–12938 (2000).
Kedersha, N. & Anderson, P. Stress granules: sites of mRNA triage that regulate mRNA stability and translatability. Biochem. Soc. Trans. 30, 963–969 (2002).
Maziuk, B. F. et al. RNA binding proteins co-localize with small tau inclusions in tauopathy. Acta Neuropathol. Commun. 6, 71 (2018). This study provides key methods for detecting RBPs associated with pathological SGs.
Li, Y. et al. Immunoprecipitation and mass spectrometry defines an extensive RBM45 protein-protein interaction network. Brain Res. 1647, 79–93 (2016).
Umoh, M. E. et al. A proteomic network approach across the ALS–FTD disease spectrum resolves clinical phenotypes and genetic vulnerability in human brain. EMBO Mol. Med. 10, 48–62 (2018).
Gunawardana, C. G. et al. The human tau interactome: binding to the ribonucleoproteome, and impaired binding of the proline-to-leucine mutant at position 301 (p301l) to chaperones and the proteasome. Mol. Cell Proteom. 14, 3000–3014 (2015).
Dhungel, N. et al. Parkinson’s disease genes VPS35 and EIF4G1 interact genetically and converge on α-synuclein. Neuron 85, 76–87 (2015).
Nichols, N. et al. EIF4G1 mutations do not cause Parkinson’s disease. Neurobiol. Aging 36, 2444.e1–4 (2015).
Kim, W. J., Kim, J. H. & Jang, S. K. Anti-inflammatory lipid mediator 15d-PGJ2 inhibits translation through inactivation of eIF4A. EMBO J. 26, 5020–5032 (2007).
Bordeleau, M. E. et al. Functional characterization of IRESes by an inhibitor of the RNA helicase eIF4A. Nat. Chem. Biol. 2, 213–220 (2006).
Cencic, R. et al. Antitumor activity and mechanism of action of the cyclopenta[b]benzofuran, silvestrol. PLOS ONE 4, e5223 (2009).
Ivanov, P., Emara, M. M., Villen, J., Gygi, S. P. & Anderson, P. Angiogenin-induced tRNA fragments inhibit translation initiation. Mol. Cell 43, 613–623 (2011).
Lyons, S. M., Achorn, C., Kedersha, N. L., Anderson, P. J. & Ivanov, P. YB-1 regulates tiRNA-induced stress granule formation but not translational repression. Nucleic Acids Res. 44, 6949–6960 (2016).
Apicco, D. J. et al. Reducing the RNA binding protein TIA1 protects against tau-mediated neurodegeneration in vivo. Nat. Neurosci. 21, 72–80 (2018). This article demonstrates that RBPs, such as TIA1, regulate the pathophysiology of tau in vivo, and also shows differential regulation of tau oligomers versus fibrils.
Armstrong, R. A., Carter, D. & Cairns, N. J. A quantitative study of the neuropathology of 32 sporadic and familial cases of frontotemporal lobar degeneration with TDP-43 proteinopathy (FTLD–TDP). Neuropathol. Appl. Neurobiol. 38, 25–38 (2012).
Janssens, J. et al. Overexpression of ALS-associated p.M337V human TDP-43 in mice worsens disease features compared to wild-type human TDP-43 mice. Mol. Neurobiol. 48, 22–35 (2013).
Figley, M. D., Bieri, G., Kolaitis, R. M., Taylor, J. P. & Gitler, A. D. Profilin 1 associates with stress granules and als-linked mutations alter stress granule dynamics. J. Neurosci. 34, 8083–8097 (2014).
Gilks, N. et al. Stress granule assembly is mediated by prion-like aggregation of TIA-1. Mol. Biol. Cell 15, 5383–5398 (2004).
Bounedjah, O. et al. Free mRNA in excess upon polysome dissociation is a scaffold for protein multimerization to form stress granules. Nucleic Acids Res. 42, 8678–8691 (2014).
Bley, N. et al. Stress granules are dispensable for mRNA stabilization during cellular stress. Nucleic Acids Res. 43, e26 (2015).
Vogler, T. O. et al. TDP-43 and RNA form amyloid-like myo-granules in regenerating muscle. Nature 563, 508–513 (2018).
Lefebvre, S. et al. Identification and characterization of a spinal muscular atrophy-determining gene. Cell 80, 155–165 (1995).
Bassell, G. J. & Warren, S. T. Fragile X syndrome: loss of local mRNA regulation alters synaptic development and function. Neuron 60, 201–214 (2008).
Kenneson, A., Zhang, F., Hagedorn, C. H. & Warren, S. T. Reduced FMRP and increased FMR1 transcription is proportionally associated with CGG repeat number in intermediate-length and premutation carriers. Hum. Mol. Genet. 10, 1449–1454 (2001).
Hagerman, P. J. & Hagerman, R. J. Fragile X-associated tremor/ataxia syndrome (FXTAS). Ment. Retard. Dev. Disabil. Res. Rev. 10, 25–30 (2004).
Neumann, M. et al. Ubiquitinated TDP-43 in frontotemporal lobar degeneration and amyotrophic lateral sclerosis. Science 314, 130–133 (2006).
Vance, C. et al. Mutations in FUS, an RNA processing protein, cause familial amyotrophic lateral sclerosis type 6. Science 323, 1208–1211 (2009).
Van Deerlin, V. M. et al. TARDBP mutations in amyotrophic lateral sclerosis with TDP-43 neuropathology: a genetic and histopathological analysis. Lancet Neurol. 7, 409–416 (2008).
Mackenzie, I. R. et al. TIA1 mutations in amyotrophic lateral sclerosis and frontotemporal dementia promote phase separation and alter stress granule dynamics. Neuron 95, 808–816 e809 (2017).
Kim, H. J. et al. Mutations in prion-like domains in hnRNPA2B1 and hnRNPA1 cause multisystem proteinopathy and ALS. Nature 495, 467–473 (2013).
Sreedharan, J. et al. TDP-43 mutations in familial and sporadic amyotrophic lateral sclerosis. Science 319, 1668–1672 (2008).
Kwiatkowski, T. J., Jr. et al. Mutations in the FUS/TLS gene on chromosome 16 cause familial amyotrophic lateral sclerosis. Science 323, 1205–1208 (2009).
Elden, A. C. et al. Ataxin-2 intermediate-length polyglutamine expansions are associated with increased risk for ALS. Nature 466, 1069–1075 (2010).
Emara, M. M. et al. Angiogenin-induced tRNA-derived stress-induced RNAs promote stress-induced stress granule assembly. J. Biol. Chem. 285, 10959–10968 (2010).
Greenway, M. J. et al. ANG mutations segregate with familial and ‘sporadic’ amyotrophic lateral sclerosis. Nat. Genet. 38, 411–413 (2006).
Dormann, D. & Haass, C. TDP-43 and FUS: a nuclear affair. Trends Neurosci. 34, 339–348 (2011).
Bosco, D. A. et al. Mutant FUS proteins that cause amyotrophic lateral sclerosis incorporate into stress granules. Hum. Mol. Genet. 19, 4160–4175 (2011).
Phillips, K., Kedersha, N., Shen, L., Blackshear, P. J. & Anderson, P. Arthritis suppressor genes TIA-1 and TTP dampen the expression of tumor necrosis factor α, cyclooxygenase 2, and inflammatory arthritis. Proc. Natl Acad. Sci. USA 101, 2011–2016 (2004).
Garaigorta, U., Heim, M. H., Boyd, B., Wieland, S. & Chisari, F. V. Hepatitis C virus (HCV) induces formation of stress granules whose proteins regulate HCV RNA replication and virus assembly and egress. J. Virol. 86, 11043–11056 (2012).
Wolozin, B. Regulated protein aggregation: stress granules and neurodegeneration. Mol. Neurodegener. 7, 56 (2012).
Kiernan, M. C. et al. Amyotrophic lateral sclerosis. Lancet 377, 942–955 (2011).
Scheltens, P. et al. Alzheimer’s disease. Lancet 388, 505–517 (2016).
Banani, S. F. et al. Compositional control of phase-separated cellular bodies. Cell 166, 651–663 (2016). This article outlines the different cellular factors controlling the formation of membraneless organelles, such as stress granules and P-bodies.
Lee, Y. et al. TIA1 variant drives myodegeneration in multisystem proteinopathy with SQSTM1 mutations. J. Clin. Invest. 128, 1164–1177 (2018).
Patel, A. et al. A liquid-to-solid phase transition of the ALS protein FUS accelerated by disease mutation. Cell 162, 1066–1077 (2015).
Molliex, A. et al. Phase separation by low complexity domains promotes stress granule assembly and drives pathological fibrillization. Cell 163, 123–133 (2015).
Hughes, M. P. et al. Atomic structures of low-complexity protein segments reveal kinked beta sheets that assemble networks. Science 359, 698–701 (2018). This study shows how different types of amino acid interactions, such as π–π and π–cation binding, control the formation of membraneless organelles and insoluble amyloids.
Ash, P. E. A. et al. Heavy metal neurotoxicants induce ALS-linked TDP-43 pathology. Toxicol. Sci. 167, 105–115, https://doi.org/10.1093/toxsci/kfy267 (2019).
Bai, B. et al. U1 small nuclear ribonucleoprotein complex and RNA splicing alterations in Alzheimer’s disease. Proc. Natl Acad. Sci. USA 110, 16562–16567 (2013). This paper shows that many RBPs accumulate as protein aggregates in AD, often in cells lacking histologically evident tau aggregates.
Vanderweyde, T. et al. Interaction of tau with the RNA-binding protein TIA1 regulates tau pathophysiology and toxicity. Cell Rep. 15, 1–12 (2016).
Vanderweyde, T. et al. Contrasting pathology of stress granule proteins TIA-1 and G3BP in tauopathies. J. Neurosci. 32, 8270–8283 (2012). This article demonstrates how tau and TIA1 interact to regulate SG biology and demonstrates that reducing TIA1 inhibits tau-mediated neurodegeneration in cultured neurons.
Zhang, Y. J. et al. Poly(GR) impairs protein translation and stress granule dynamics in C9orf72-associated frontotemporal dementia and amyotrophic lateral sclerosis. Nat. Med. 24, 1136–1142 (2018).
Ash, P. E. et al. Unconventional translation of C9ORF72 GGGGCC expansion generates insoluble polypeptides specific to c9FTD/ALS. Neuron 77, 639–646 (2013).
Green, K. M. et al. RAN translation at C9orf72-associated repeat expansions is selectively enhanced by the integrated stress response. Nat. Commun. 8, 2005 (2017).
Boeynaems, S. et al. Phase separation of c9orf72 dipeptide repeats perturbs stress granule dynamics. Mol. Cell 65, 1044–1055.e1045 (2017).
Lee, K. H. et al. C9orf72 dipeptide repeats impair the assembly, dynamics, and function of membrane-less organelles. Cell 167, 774–788.e717 (2016). This study shows how an extended dipeptide repeat can disrupt SG biology.
Gasset-Rosa, F. et al. Cytoplasmic TDP-43 de-mixing independent of stress granules drives inhibition of nuclear import, loss of nuclear TDP-43, and cell death. Neuron 102, 339–357.e7 (2019). This article demonstrates that, in cells, TDP43 aggregates pass through a SG phase transiently before evolving into pathological aggregates.
Mann, J. R. et al. RNA binding antagonizes neurotoxic phase transitions of TDP-43. Neuron 102, 321–338.e8 (2019).
McGurk, L. et al. Poly(ADP–ribose) prevents pathological phase separation of TDP-43 by promoting liquid demixing and stress granule localization. Mol. Cell 71, 703–717 e709 (2018).
Brettschneider, J. et al. TDP-43 pathology and neuronal loss in amyotrophic lateral sclerosis spinal cord. Acta Neuropathol. 128, 423–437 (2014).
Zhang, K. et al. The C9orf72 repeat expansion disrupts nucleocytoplasmic transport. Nature 525, 56–61 (2015).
Chou, C. C. et al. TDP-43 pathology disrupts nuclear pore complexes and nucleocytoplasmic transport in ALS/FTD. Nat. Neurosci. 21, 228–239 (2018).
Afroz, T. et al. Functional and dynamic polymerization of the ALS-linked protein TDP-43 antagonizes its pathologic aggregation. Nat. Commun. 8, 45 (2017).
Hanger, D. P., Hughes, K., Woodgett, J. R., Brion, J. P. & Anderton, B. H. Glycogen synthase kinase-3 induces Alzheimer’s disease-like phosphorylation of tau: generation of paired helical filament epitopes and neuronal localisation of the kinase. Neurosci. Lett. 147, 58–62 (1992).
Baumann, K., Mandelkow, E., Biernat, J., Piwnica-Worms, H. & Mandelkow, E. Abnormal Alzheimer-like phosphorylation of tau-protein by cyclin-dependent kinases cdk2 and cdk5. FEBS Lett. 336, 417–424 (1993).
Timm, T., Marx, A., Panneerselvam, S., Mandelkow, E. & Mandelkow, E. M. Structure and regulation of MARK, a kinase involved in abnormal phosphorylation of Tau protein. BMC Neurosci. 9, S9 (2008).
Trinczek, B., Biernat, J., Baumann, K., Mandelkow, E. M. & Mandelkow, E. Domains of tau protein, differential phosphorylation, and dynamic instability of microtubules. Mol. Biol. Cell 6, 1887–1902 (1995).
Zempel, H. et al. Amyloid-beta oligomers induce synaptic damage via Tau-dependent microtubule severing by TTLL6 and spastin. EMBO J. 32, 2920–2937 (2013).
Kampers, T., Friedhoff, P., Biernat, J., Mandelkow, E. M. & Mandelkow, E. RNA stimulates aggregation of microtubule-associated protein tau into Alzheimer-like paired helical filaments. FEBS Lett. 399, 344–349 (1996).
Fitzpatrick, A. W. P. et al. Cryo-EM structures of tau filaments from Alzheimer’s disease. Nature 547, 185–190 (2017).
Friedhoff, P., Schneider, A., Mandelkow, E. M. & Mandelkow, E. Rapid assembly of Alzheimer-like paired helical filaments from microtubule-associated protein tau monitored by fluorescence in solution. Biochemistry 37, 10223–10230 (1998).
Wilson, D. M. & Binder, L. I. Free fatty acids stimulate the polymerization of tau and amyloid beta peptides: in vitro evidence for a common effector of pathogenesis in Alzheimer’s disease. Am. J. Pathol. 150, 2181–2195 (1997).
Zhang, X. et al. RNA stores tau reversibly in complex coacervates. PLOS Biol. 15, e2002183 (2017).
Wegmann, S. et al. Tau protein liquid–liquid phase separation can initiate tau aggregation. EMBO J. 37, e98049 (2018). This article provides a detailed characterization of the biophysical factors controlling tau phase separation.
Meier, S. et al. Pathological tau promotes neuronal damage by impairing ribosomal function and decreasing protein synthesis. J. Neurosci. 36, 1001–1007 (2016).
Wang, P. et al. Tau interactome mapping based identification of Otub1 as Tau deubiquitinase involved in accumulation of pathological Tau forms in vitro and in vivo. Acta Neuropathol. 133, 731–749 (2017).
Eftekharzadeh, B. et al. Tau protein disrupts nucleocytoplasmic transport in Alzheimer’s disease. Neuron 99, 925–940 e927 (2018).
Silva, J. M. et al. Dysregulation of autophagy and stress granule-related proteins in stress-driven Tau pathology. Cell Death Differ. 171, 1411–1427 (2019). This paper demonstrates that behaviourally stressful experiences can elicit the biochemical changes associated with the translational stress response in the brain.
Cairns, N. J. et al. TDP-43 in familial and sporadic frontotemporal lobar degeneration with ubiquitin inclusions. Am. J. Pathol. 171, 227–240 (2007).
Moujalled, D. et al. Phosphorylation of hnRNP K by cyclin-dependent kinase 2 controls cytosolic accumulation of TDP-43. Hum. Mol. Genet. 24, 1655–1669 (2015).
Jiang, L. et al. TIA1 regulates the generation and response to toxic tau oligomers. Acta Neuropathol. 137, 259–277 (2019). This article demonstrates that tau oligomers and fibrils both propagate pathology in vivo, but that only tau oligomers stimulate the accumulation of tau-associated SGs and cause neurodegeneration.
Sanders, D. W. et al. Distinct tau prion strains propagate in cells and mice and define different tauopathies. Neuron 82, 1271–1288 (2014).
Liu, L. et al. Trans-synaptic spread of tau pathology in vivo. PLOS ONE 7, e31302 (2012).
Smethurst, P. et al. In vitro prion-like behaviour of TDP-43 in ALS. Neurobiol Dis. 96, 236–247 (2016).
Asai, H. et al. Depletion of microglia and inhibition of exosome synthesis halt tau propagation. Nat. Neurosci. 18, 1584–1593 (2015).
Ghosh, S. & Geahlen, R. L. Stress granules modulate SYK to cause microglial cell dysfunction in Alzheimer’s disease. EBioMedicine 2, 1785–1798 (2015).
Guerreiro, R. et al. TREM2 variants in Alzheimer’s disease. N. Engl. J. Med. 368, 117–127 (2013).
Pimenova, A. A., Raj, T. & Goate, A. M. Untangling genetic risk for Alzheimer’s disease. Biol. Psychiatry 83, 300–310 (2018).
Roberson, E. D. et al. Reducing endogenous tau ameliorates amyloid beta-induced deficits in an Alzheimer’s disease mouse model. Science 316, 750–754 (2007).
Vossel, K. A. et al. Tau reduction prevents Aβ-induced defects in axonal transport. Science 330, 198 (2010).
Cruts, M. et al. Null mutations in progranulin cause ubiquitin-positive frontotemporal dementia linked to chromosome 17q21. Nature 442, 920–924 (2006).
Melamed, Z. et al. Premature polyadenylation-mediated loss of stathmin-2 is a hallmark of TDP-43-dependent neurodegeneration. Nat. Neurosci. 22, 180–190 (2019).
Klim, J. R. et al. ALS-implicated protein TDP-43 sustains levels of STMN2, a mediator of motor neuron growth and repair. Nat. Neurosci. 22, 167–179 (2019).
Nguyen, H. P., Van Broeckhoven, C. & van der Zee, J. ALS genes in the genomic era and their implications for FTD. Trends Genet. 34, 404–423 (2018).
Deng, H. X. et al. Mutations in UBQLN2 cause dominant X-linked juvenile and adult-onset ALS and ALS/dementia. Nature 477, 211–215 (2011).
Watts, G. D. et al. Inclusion body myopathy associated with Paget disease of bone and frontotemporal dementia is caused by mutant valosin-containing protein. Nat. Genet. 36, 377–381 (2004).
Fecto, F. et al. SQSTM1 mutations in familial and sporadic amyotrophic lateral sclerosis. Arch. Neurol. 68, 1440–1446 (2011).
Cirulli, E. T. et al. Exome sequencing in amyotrophic lateral sclerosis identifies risk genes and pathways. Science 347, 1436–1441 (2015).
Freischmidt, A. et al. Haploinsufficiency of TBK1 causes familial ALS and fronto-temporal dementia. Nat. Neurosci. 18, 631–636 (2015).
Weidberg, H. & Elazar, Z. TBK1 mediates crosstalk between the innate immune response and autophagy. Sci. Signal. 4, pe39 (2011).
Skibinski, G. et al. Mutations in the endosomal ESCRTIII-complex subunit CHMP2B in frontotemporal dementia. Nat. Genet. 37, 806–808 (2005).
Gilpin, K. M., Chang, L. & Monteiro, M. J. ALS-linked mutations in ubiquilin-2 or hnRNPA1 reduce interaction between ubiquilin-2 and hnRNPA1. Hum. Mol. Genet. 24, 2565–2577 (2015).
Cassel, J. A. & Reitz, A. B. Ubiquilin-2 (UBQLN2) binds with high affinity to the C-terminal region of TDP-43 and modulates TDP-43 levels in H4 cells: characterization of inhibition by nucleic acids and 4-aminoquinolines. Biochim. Biophys. Acta 1834, 964–971 (2013).
Buchan, J. R., Kolaitis, R. M., Taylor, J. P. & Parker, R. Eukaryotic stress granules are cleared by autophagy and CDC48/VCP function. Cell 153, 1461–1474 (2013).
Hutton, M. et al. Association of missense and 5′-splice-site mutations in tau with the inherited dementia FTDP-17. Nature 393, 702–705 (1998).
Nicolas, A. et al. Genome-wide analyses identify KIF5A as a novel ALS gene. Neuron 97, 1268–1283.e1266 (2018).
Wu, C. H. et al. Mutations in the profilin 1 gene cause familial amyotrophic lateral sclerosis. Nature 488, 499–503 (2012).
Puls, I. et al. Mutant dynactin in motor neuron disease. Nat. Genet. 33, 455–456 (2003).
Smith, B. N. et al. Exome-wide rare variant analysis identifies TUBA4A mutations associated with familial ALS. Neuron 84, 324–331 (2014).
Munch, C. et al. Point mutations of the p150 subunit of dynactin (DCTN1) gene in ALS. Neurology 63, 724–726 (2004).
Landers, J. E. et al. Reduced expression of the kinesin-associated protein 3 (KIFAP3) gene increases survival in sporadic amyotrophic lateral sclerosis. Proc. Natl Acad. Sci. USA 106, 9004–9009 (2009).
Magnani, E. et al. Interaction of tau protein with the dynactin complex. EMBO J. 26, 4546–4554 (2007).
Ransohoff, R. M. How neuroinflammation contributes to neurodegeneration. Science 353, 777–783 (2016).
Bemiller, S. M. et al. TREM2 deficiency exacerbates tau pathology through dysregulated kinase signaling in a mouse model of tauopathy. Mol. Neurodegener. 12, 74 (2017).
Broce, I. et al. Immune-related genetic enrichment in frontotemporal dementia: an analysis of genome-wide association studies. PLOS Med. 15, e1002487 (2018).
Becker, L. A. et al. Therapeutic reduction of ataxin-2 extends lifespan and reduces pathology in TDP-43 mice. Nature 544, 367–371 (2017). This study demonstrates that therapeutic reduction of ATXN2 delays the progression of TDP43-induced neurodegeneration in vivo.
Zhang, K. et al. Stress granule assembly disrupts nucleocytoplasmic transport. Cell 173, 958–971.e917 (2018). This article demonstrates a closely linked relationship between the accumulation of SGs and disruption of nuclear pore biology.
Smith, H. L. & Mallucci, G. R. The unfolded protein response: mechanisms and therapy of neurodegeneration. Brain 139, 2113–2121 (2016).
Moreno, J. A. et al. Sustained translational repression by eIF2α-P mediates prion neurodegeneration. Nature 485, 507–511 (2012). This study demonstrates that reducing eIF2α phosphorylation in vivo decreases neurodegeneration mediated by prions.
Ma, T. et al. Suppression of eIF2α kinases alleviates Alzheimer’s disease-related plasticity and memory deficits. Nat. Neurosci. 16, 1299–1305 (2013).
Khurana, V. et al. TOR-mediated cell-cycle activation causes neurodegeneration in a Drosophila tauopathy model. Curr. Biol. 16, 230–241 (2006).
Wang, I. F. et al. Autophagy activators rescue and alleviate pathogenesis of a mouse model with proteinopathies of the TAR DNA-binding protein 43. Proc. Natl Acad. Sci. USA 109, 15024–15029 (2012).
Martinez, F. J. et al. Protein–RNA networks regulated by normal and ALS-associated mutant HnRNPA2B1 in the nervous system. Neuron 92, 780–795 (2016).
Walter, H. & Brooks, D. E. Phase separation in cytoplasm, due to macromolecular crowding, is the basis for microcompartmentation. FEBS Lett. 361, 135–139 (1995).
Toombs, J. A. et al. De novo design of synthetic prion domains. Proc. Natl Acad. Sci. USA 109, 6519–6524 (2012).
Prilusky, J. et al. FoldIndex: a simple tool to predict whether a given protein sequence is intrinsically unfolded. Bioinformatics 21, 3435–3438 (2005).
Wei, M. T. et al. Phase behaviour of disordered proteins underlying low density and high permeability of liquid organelles. Nat. Chem. 9, 1118–1125 (2017).
Wang, J. et al. A molecular grammar governing the driving forces for phase separation of prion-like RNA binding proteins. Cell 174, 688–699.e616 (2018).
Bergeron-Sandoval, L. P., Safaee, N. & Michnick, S. W. Mechanisms and consequences of macromolecular phase separation. Cell 165, 1067–1079 (2016).
Feric, M. et al. Coexisting liquid phases underlie nucleolar subcompartments. Cell 165, 1686–1697 (2016). This article elegantly demonstrates that the nucleolus exists as a phase-separated structure, as well as demonstrating many key methods used in the field.
Prum, R. O., Dufresne, E. R., Quinn, T. & Waters, K. Development of colour-producing β-keratin nanostructures in avian feather barbs. J. R. Soc. Interface 6 (Suppl. 2), S253–S265 (2009).
Milovanovic, D., Wu, Y., Bian, X. & De Camilli, P. A liquid phase of synapsin and lipid vesicles. Science 361, 604–607 (2018).
Li, P. et al. Phase transitions in the assembly of multivalent signalling proteins. Nature 483, 336–340 (2012).
Hnisz, D., Shrinivas, K., Young, R. A., Chakraborty, A. K. & Sharp, P. A. A phase separation model for transcriptional control. Cell 169, 13–23 (2017).
Youn, J. Y. et al. High-density proximity mapping reveals the subcellular organization of mRNA-associated granules and bodies. Mol. Cell 69, 517–532.e511 (2018).
Wolozin, B. The evolution of phase-separated TDP-43 in stress. Neuron 102, 265–267 (2019).
Author information
Authors and Affiliations
Contributions
B.W. researched data for the article. B.W. and P.I. provided substantial contributions to discussion of the article’s content, wrote the article, and reviewed and edited the manuscript before submission.
Corresponding author
Ethics declarations
Competing interests
B.W. is co-founder and chief scientific officer for Aquinnah Pharmaceuticals Inc. P.I. declares no competing interests.
Additional information
Peer review information
Nature Reviews Neuroscience thanks E. Buratti and the other, anonymous, reviewer(s) for their contribution to the peer review of this work.
Publisher’s note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Glossary
- Membraneless organelles
-
Macromolecular complexes composed of a large group of proteins that carry out specific functions and typically are observable via microscopy. Classic membraneless organelles are RNA granules and nuclear bodies that contain RNA-binding proteins and RNA.
- Frontotemporal dementia
-
(FTD). An age-related degenerative disease in which neurons of the frontal cortex degenerate, commonly producing behavioural dysinhibition, followed ultimately by death. FTD most commonly occurs sporadically, but genetic forms are most frequently caused by mutations causing progranulin haploinsufficiency, mutations in MAPT (which encodes tau) or expansions of the G4C2 hexanucleotide repeat domain of C9ORF72.
- Intrinsically disordered protein regions
-
Regions in proteins that have a low propensity to form secondary structures, such as α-helices or β-sheets. These regions often contain hydrophobic or low-complexity domains, and have a high propensity to aggregate.
- Amyloid-β
-
(Aβ). A 4-kD peptide that is generated by cleavage of the amyloid precursor protein and accumulates as neuritic plaques in Alzheimer disease.
- RNA recognition motifs
-
Domains that are present in RBPs that recognize a consensus sequence of RNA. The consensus sequence is typically single-stranded and about six to eight bases long. RBPs typically have one to three RNA recognition motifs.
- Pre-initiation complexes
-
(PICs). PICs contain mRNA, the 40S ribosomal complex and associated translation initiation factors. Under optimal conditions, the PIC combines with the 60S ribosomal subunit to produce 80S ribosomes, which enables the translation of nascent proteins. Under stress, the PIC is bound by other RNA-binding proteins, promoting stress granule formation.
- Polysomes
-
Complexes (also known as polyribosomes) on mRNA molecules that are formed by two or more ribosomes that are synchronously producing a new protein. The polysome represents the most actively translating fraction of a translational complex.
- 40S ribosomal subunit
-
A small subunit of the eukaryotic 80S ribosome that contains multiple ribosomal proteins designated by the term RPS, and that is a fundamental component of the pre-initiation complex, which binds mRNAs and interacts with translation initiation factors. The 40S subunit plays a key role in recognition of the start AUG codon on mRNA.
- tRNA-derived stress-induced RNAs
-
(tiRNAs). Small non-coding RNAs produced by the ribonuclease angiogenin in response to stress. They represent the 5′ and 3′ halves of mature cytoplasmic tRNAs and regulate multiple aspects of RNA metabolism, including protein synthesis and stress granule formation.
- Low-complexity domains
-
(LCDs). Protein domains that contain a small number of different types of amino acids. The LCDs that characterize RNA-binding proteins tend to contain alanine, glycine, glutamine and proline residues.
- Chronic traumatic encephalopathy
-
A type of neurodegeneration that appears years after exposure to brain trauma, typically resulting from repetitive insults; it is characterized by the presence of neurofibrillary tangles or aggregated TAR DNA-binding protein 43. The pathology tends to begin at the bases of neuronal sulci where the physical force of the trauma was concentrated.
- Oligomers
-
Small complexes composed of 2 to ~10 subunits of the same protein that are tightly associated in a repetitive manner. Oligomers appear to be more toxic than fibrils, perhaps because oligomers are smaller and more mobile than fibrils.
- Fibrils
-
A large macromolecular complex of proteins that stack in a regular array of repetitive oligomers. Multiple fibrils commonly coalesce to form the hallmark structures of aggregated proteins that are observed in individuals with neurodegenerative diseases.
- β-sheet
-
A highly stable protein structure that can stack to form large macromolecular fibrils.
- Low-complexity aromatic-rich kinked segments
-
These segments exhibit a moderate affinity for like regions and might be a chemical structure that enables liquid–liquid phase separation. Their moderate affinity promotes a dynamic association that advances the coalescence of like proteins in granules that still exhibit extensive protein movement.
- 60S ribosomal subunit
-
The large subunit of the eukaryotic 80S ribosome, which contains ribosomal proteins that are designated by the term RPL and attaches to translationally competent PICs. It contains a peptidyl transferase centre, catalysing the addition of amino acids onto the nascent peptides during translation.
- Propagation
-
The process by which disease pathology spreads among neurons in a cell-dependent manner. With propagation, a pathological aggregate secreted by a cell (classically a neuron or microglial cell) or injected into the neuropile seeds a similar aggregate in adjacent cells. These cells can then form new aggregated protein from endogenous stores of the same protein, secrete the newly aggregated protein and seed aggregation in yet another cell. In this manner, disease pathology can propagate via multiple stages of progressive seeding.
- Templating
-
A process in which a particular conformation of a protein acts to induce a similar conformation in like proteins with which it comes in contact.
Rights and permissions
About this article
Cite this article
Wolozin, B., Ivanov, P. Stress granules and neurodegeneration. Nat Rev Neurosci 20, 649–666 (2019). https://doi.org/10.1038/s41583-019-0222-5
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1038/s41583-019-0222-5
This article is cited by
-
Physiology and pharmacological targeting of phase separation
Journal of Biomedical Science (2024)
-
Regulation of stress granule formation in human oligodendrocytes
Nature Communications (2024)
-
SUMOylation modulates eIF5A activities in both yeast and pancreatic ductal adenocarcinoma cells
Cellular & Molecular Biology Letters (2024)
-
Cyclophilin A supports translation of intrinsically disordered proteins and affects haematopoietic stem cell ageing
Nature Cell Biology (2024)
-
ALS-linked FUS R521C disrupts arginine methylation of UBAP2L and stress granule dynamics
Journal of Analytical Science and Technology (2023)
