Bridging biophysics and neurology: aberrant phase transitions in neurodegenerative disease (original) (raw)
Ghasemi, M. & Brown, R. H. Jr. Genetics of amyotrophic lateral sclerosis. Cold Spring Harb. Perspect. Med.8, a024125 (2018). PubMedPubMed Central Google Scholar
Taylor, J. P., Brown, R. H. Jr & Cleveland, D. W. Decoding ALS: from genes to mechanism. Nature539, 197–206 (2016). PubMedPubMed Central Google Scholar
Barmada, S. J. Linking RNA dysfunction and neurodegeneration in amyotrophic lateral sclerosis. Neurotherapeutics12, 340–351 (2015). CASPubMedPubMed Central Google Scholar
Sreedharan, J. et al. TDP-43 mutations in familial and sporadic amyotrophic lateral sclerosis. Science319, 1668–1672 (2008). CASPubMedPubMed Central Google Scholar
Kabashi, E. et al. TARDBP mutations in individuals with sporadic and familial amyotrophic lateral sclerosis. Nat. Genet.40, 572–574 (2008). CASPubMed Google Scholar
Vance, C. et al. Mutations in FUS, an RNA processing protein, cause familial amyotrophic lateral sclerosis type 6. Science323, 1208–1211 (2009). CASPubMedPubMed Central Google Scholar
Kwiatkowski, T. J. Jr. et al. Mutations in the FUS/TLS gene on chromosome 16 cause familial amyotrophic lateral sclerosis. Science323, 1205–1208 (2009). CASPubMed Google Scholar
Kim, H. J. et al. Mutations in prion-like domains in hnRNPA2B1 and hnRNPA1 cause multisystem proteinopathy and ALS. Nature495, 467–473 (2013). CASPubMedPubMed Central Google Scholar
Liu, Q. et al. Whole-exome sequencing identifies a missense mutation in hnRNPA1 in a family with flail arm ALS. Neurology87, 1763–1769 (2016). CASPubMed Google Scholar
Vieira, N. M. et al. A defect in the RNA-processing protein HNRPDL causes limb-girdle muscular dystrophy 1G (LGMD1G). Hum. Mol. Genet.23, 4103–4110 (2014). CASPubMed Google Scholar
Johnson, J. O. et al. Mutations in the matrin 3 gene cause familial amyotrophic lateral sclerosis. Nat. Neurosci.17, 664–666 (2014). CASPubMedPubMed Central Google Scholar
Mackenzie, I. R. et al. TIA1 mutations in amyotrophic lateral sclerosis and frontotemporal dementia promote phase separation and alter stress granule dynamics. Neuron95, 808–816 (2017). CASPubMedPubMed Central Google Scholar
Smith, B. N. et al. Mutations in the vesicular trafficking protein annexin A11 are associated with amyotrophic lateral sclerosis. Sci. Transl Med.9, eaad9157 (2017). PubMedPubMed Central Google Scholar
Buchan, J. R. mRNP granules. Assembly, function, and connections with disease. RNA Biol.11, 1019–1030 (2014). PubMedPubMed Central Google Scholar
Kiebler, M. A. & Bassell, G. J. Neuronal RNA granules: movers and makers. Neuron51, 685–690 (2006). CASPubMed Google Scholar
Shin, Y. & Brangwynne, C. P. Liquid phase condensation in cell physiology and disease. Science357, eaaf4382 (2017). PubMed Google Scholar
Langdon, E. M. & Gladfelter, A. S. A new lens for RNA localization: liquid-liquid phase separation. Annu. Rev. Microbiol.72, 255–271 (2018). CASPubMed Google Scholar
Zacharias, E. Über den Nucleolus. Botan. Zeit.43, 257 (1885). Google Scholar
Walter, H. & Brooks, D. E. Phase separation in cytoplasm, due to macromolecular crowding, is the basis for microcompartmentation. FEBS Lett.361, 135–139 (1995). CASPubMed Google Scholar
Banani, S. F., Lee, H. O., Hyman, A. A. & Rosen, M. K. Biomolecular condensates: organizers of cellular biochemistry. Nat. Rev. Mol. Cell Biol.18, 285–298 (2017). CASPubMedPubMed Central Google Scholar
Altmeyer, M. et al. Liquid demixing of intrinsically disordered proteins is seeded by poly(ADP-ribose). Nat. Commun.6, 8088 (2015). CASPubMed Google Scholar
Larson, A. G. et al. Liquid droplet formation by HP1α suggests a role for phase separation in heterochromatin. Nature547, 236–240 (2017). CASPubMedPubMed Central Google Scholar
Cerase, A., Armaos, A., Cid, F., Avner, P. & Tartaglia, G. G. Xist lncRNA forms silencing granules that induce heterochromatin formation and repressive complexes recruitment by phase separation. Preprint at bioRxivhttps://www.biorxiv.org/content/10.1101/351015v1 (2018).
Brangwynne, C. P., Mitchison, T. J. & Hyman, A. A. Active liquid-like behavior of nucleoli determines their size and shape in Xenopus laevis oocytes. Proc. Natl Acad. Sci. USA108, 4334–4339 (2011). CASPubMedPubMed Central Google Scholar
Sheu-Gruttadauria, J. & MacRae, I. J. Phase transitions in the assembly and function of human miRISC. Cell173, 946–957 (2018). CASPubMedPubMed Central Google Scholar
Schmidt, H. B. & Gorlich, D. Nup98 FG domains from diverse species spontaneously phase-separate into particles with nuclear pore-like permselectivity. eLife4, e04251 (2015). PubMed Central Google Scholar
Jiang, H. et al. Phase transition of spindle-associated protein regulate spindle apparatus assembly. Cell163, 108–122 (2015). CASPubMedPubMed Central Google Scholar
Banjade, S. & Rosen, M. K. Phase transitions of multivalent proteins can promote clustering of membrane receptors. eLife3, e04123 (2014). PubMed Central Google Scholar
Winton, M. J. et al. Disturbance of nuclear and cytoplasmic TAR DNA-binding protein (TDP-43) induces disease-like redistribution, sequestration, and aggregate formation. J. Biol. Chem.283, 13302–13309 (2008). CASPubMedPubMed Central Google Scholar
Johnson, B. S. et al. TDP-43 is intrinsically aggregation-prone, and amyotrophic lateral sclerosis-linked mutations accelerate aggregation and increase toxicity. J. Biol. Chem.284, 20329–20339 (2009). CASPubMedPubMed Central Google Scholar
Sun, Z. et al. Molecular determinants and genetic modifiers of aggregation and toxicity for the ALS disease protein FUS/TLS. PLOS Biol.9, e1000614 (2011). CASPubMedPubMed Central Google Scholar
Kato, M. et al. Cell-free formation of RNA granules: low complexity sequence domains form dynamic fibers within hydrogels. Cell149, 753–767 (2012). CASPubMedPubMed Central Google Scholar
Van Treeck, B. & Parker, R. Emerging roles for intermolecular RNA-RNA interactions in RNP assemblies. Cell174, 791–802 (2018). PubMedPubMed Central Google Scholar
McGurk, L. et al. Poly(ADP-ribose) prevents pathological phase separation of TDP-43 by promoting liquid demixing and stress granule localization. Mol. Cell71, 703–717 (2018). CASPubMedPubMed Central Google Scholar
Patel, A. et al. ATP as a biological hydrotrope. Science356, 753–756 (2017). CASPubMed Google Scholar
King, O. D., Gitler, A. D. & Shorter, J. The tip of the iceberg: RNA-binding proteins with prion-like domains in neurodegenerative disease. Brain Res.1462, 61–80 (2012). CASPubMedPubMed Central Google Scholar
Lin, Y., Protter, D. S., Rosen, M. K. & Parker, R. Formation and maturation of phase-separated liquid droplets by RNA-binding proteins. Mol. Cell60, 208–219 (2015). CASPubMedPubMed Central Google Scholar
Molliex, A. et al. Phase separation by low complexity domains promotes stress granule assembly and drives pathological fibrillization. Cell163, 123–133 (2015). CASPubMedPubMed Central Google Scholar
Brangwynne, C. P., Tompa, P. & Pappu, R. V. Polymer physics of intracellular phase transitions. Nat. Phys.11, 899 (2015). CAS Google Scholar
Wang, J. et al. A molecular grammar governing the driving forces for phase separation of prion-like RNA binding proteins. Cell174, 688–699 (2018). CASPubMedPubMed Central Google Scholar
Conicella, A. E., Zerze, G. H., Mittal, J. & Fawzi, N. L. ALS mutations disrupt phase separation mediated by alpha-helical structure in the TDP-43 low-complexity C-terminal domain. Structure24, 1537–1549 (2016). CASPubMedPubMed Central Google Scholar
Ryan, V. H. et al. Mechanistic view of hnRNPA2 low-complexity domain structure, interactions, and phase separation altered by mutation and arginine methylation. Mol. Cell69, 465–479 (2018). CASPubMedPubMed Central Google Scholar
Hughes, M. P. et al. Atomic structures of low-complexity protein segments reveal kinked beta sheets that assemble networks. Science359, 698–701 (2018). CASPubMedPubMed Central Google Scholar
Guenther, E. L. et al. Atomic structures of TDP-43 LCD segments and insights into reversible or pathogenic aggregation. Nat. Struct. Mol. Biol.25, 463–471 (2018). CASPubMedPubMed Central Google Scholar
Jain, S. et al. ATPase-modulated stress granules contain a diverse proteome and substructure. Cell164, 487–498 (2016). CASPubMedPubMed Central Google Scholar
Kosik, K. S. & Krichevsky, A. M. The message and the messenger: delivering RNA in neurons. Sci. STKE2002, e16 (2002). Google Scholar
Vogler, T. O. et al. TDP-43 and RNA form amyloid-like myo-granules in regenerating muscle. Nature563, 508–513 (2018). CASPubMedPubMed Central Google Scholar
Neumann, M. et al. Ubiquitinated TDP-43 in frontotemporal lobar degeneration and amyotrophic lateral sclerosis. Science314, 130–133 (2006). CASPubMed Google Scholar
Salajegheh, M. et al. Sarcoplasmic redistribution of nuclear TDP-43 in inclusion body myositis. Muscle Nerve40, 19–31 (2009). CASPubMedPubMed Central Google Scholar
Weihl, C. C. et al. TDP-43 accumulation in inclusion body myopathy muscle suggests a common pathogenic mechanism with frontotemporal dementia. J. Neurol. Neurosurg. Psychiatry79, 1186–1189 (2008). CASPubMed Google Scholar
Irwin, D. J. et al. Frontotemporal lobar degeneration: defining phenotypic diversity through personalized medicine. Acta Neuropathol.129, 469–491 (2015). PubMed Google Scholar
Kanekura, K. et al. Poly-dipeptides encoded by the C9orf72 repeats block global protein translation. Hum. Mol. Genet.25, 1803–1813 (2016). CASPubMedPubMed Central Google Scholar
Deshaies, J. E. et al. TDP-43 regulates the alternative splicing of hnRNP A1 to yield an aggregation-prone variant in amyotrophic lateral sclerosis. Brain141, 1320–1333 (2018). PubMedPubMed Central Google Scholar
Deng, H. X. et al. FUS-immunoreactive inclusions are a common feature in sporadic and non-SOD1 familial amyotrophic lateral sclerosis. Ann. Neurol.67, 739–748 (2010). CASPubMedPubMed Central Google Scholar
Dormann, D. et al. ALS-associated fused in sarcoma (FUS) mutations disrupt transportin-mediated nuclear import. EMBO J.29, 2841–2857 (2010). CASPubMedPubMed Central Google Scholar
Lu, L. et al. Amyotrophic lateral sclerosis-linked mutant SOD1 sequesters Hu antigen R (HuR) and TIA-1-related protein (TIAR): implications for impaired post-transcriptional regulation of vascular endothelial growth factor. J. Biol. Chem.284, 33989–33998 (2009). CASPubMedPubMed Central Google Scholar
Volkening, K., Leystra-Lantz, C., Yang, W., Jaffee, H. & Strong, M. J. TAR DNA binding protein of 43 kDa (TDP-43), 14-3-3 proteins and copper/zinc superoxide dismutase (SOD1) interact to modulate NFL mRNA stability. Implications for altered RNA processing in amyotrophic lateral sclerosis (ALS). Brain Res.1305, 168–182 (2009). CASPubMed Google Scholar
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 ONE5, e13250 (2010). PubMedPubMed Central Google Scholar
Elden, A. C. et al. Ataxin-2 intermediate-length polyglutamine expansions are associated with increased risk for ALS. Nature466, 1069–1075 (2010). CASPubMedPubMed Central Google Scholar
Deng, H. X. et al. Mutations in UBQLN2 cause dominant X-linked juvenile and adult-onset ALS and ALS/dementia. Nature477, 211–215 (2011). CASPubMedPubMed Central Google Scholar
Neumann, M. et al. A new subtype of frontotemporal lobar degeneration with FUS pathology. Brain132, 2922–2931 (2009). PubMedPubMed Central Google Scholar
Maruyama, H. et al. Mutations of optineurin in amyotrophic lateral sclerosis. Nature465, 223–226 (2010). CASPubMed Google Scholar
Schroder, R. et al. Mutant valosin-containing protein causes a novel type of frontotemporal dementia. Ann. Neurol.57, 457–461 (2005). PubMed Google Scholar
Wilson, A. C., Dugger, B. N., Dickson, D. W. & Wang, D. S. TDP-43 in aging and Alzheimer’s disease — a review. Int. J. Clin. Exp. Pathol.4, 147–155 (2011). CASPubMedPubMed Central Google Scholar
Schwab, C., Arai, T., Hasegawa, M., Yu, S. & McGeer, P. L. Colocalization of transactivation-responsive DNA-binding protein 43 and huntingtin in inclusions of Huntington disease. J. Neuropathol. Exp. Neurol.67, 1159–1165 (2008). PubMed Google Scholar
Uryu, K. et al. Concomitant TAR-DNA-binding protein 43 pathology is present in Alzheimer disease and corticobasal degeneration but not in other tauopathies. J. Neuropathol. Exp. Neurol.67, 555–564 (2008). CASPubMed Google Scholar
Nakashima-Yasuda, H. et al. Co-morbidity of TDP-43 proteinopathy in Lewy body related diseases. Acta Neuropathol.114, 221–229 (2007). CASPubMed Google Scholar
Lippa, C. F. et al. Transactive response DNA-binding protein 43 burden in familial Alzheimer disease and Down syndrome. Arch. Neurol.66, 1483–1488 (2009). PubMedPubMed Central Google Scholar
Chanson, J. B. et al. TDP43-positive intraneuronal inclusions in a patient with motor neuron disease and Parkinson’s disease. Neurodegener. Dis.7, 260–264 (2010). PubMed Google Scholar
Gallego-Iradi, M. C. et al. Subcellular localization of matrin 3 containing mutations associated with ALS and distal myopathy. PLOS ONE10, e0142144 (2015). PubMedPubMed Central Google Scholar
Couthouis, J. et al. A yeast functional screen predicts new candidate ALS disease genes. Proc. Natl Acad. Sci. USA108, 20881–20890 (2011). CASPubMedPubMed Central Google Scholar
Couthouis, J. et al. Evaluating the role of the FUS/TLS-related gene EWSR1 in amyotrophic lateral sclerosis. Hum. Mol. Genet.21, 2899–2911 (2012). CASPubMedPubMed Central Google Scholar
Freibaum, B. D., Chitta, R. K., High, A. A. & Taylor, J. P. Global analysis of TDP-43 interacting proteins reveals strong association with RNA splicing and translation machinery. J. Proteome Res.9, 1104–1120 (2010). CASPubMedPubMed Central Google Scholar
Andersen, J. S. et al. Directed proteomic analysis of the human nucleolus. Curr. Biol.12, 1–11 (2002). PubMed Google Scholar
Shelkovnikova, T. A., Robinson, H. K., Troakes, C., Ninkina, N. & Buchman, V. L. Compromised paraspeckle formation as a pathogenic factor in FUSopathies. Hum. Mol. Genet.23, 2298–2312 (2014). CASPubMed Google Scholar
Rajgor, D., Hanley, J. G. & Shanahan, C. M. Identification of novel nesprin-1 binding partners and cytoplasmic matrin-3 in processing bodies. Mol. Biol. Cell27, 3894–3902 (2016). CASPubMedPubMed Central Google Scholar
Yamazaki, T. et al. FUS-SMN protein interactions link the motor neuron diseases ALS and SMA. Cell Rep.2, 799–806 (2012). CASPubMedPubMed Central Google Scholar
Wang, I. F., Reddy, N. M. & Shen, C. K. Higher order arrangement of the eukaryotic nuclear bodies. Proc. Natl Acad. Sci. USA99, 13583–13588 (2002). CASPubMedPubMed Central Google Scholar
Ishihara, T. et al. Decreased number of Gemini of coiled bodies and U12 snRNA level in amyotrophic lateral sclerosis. Hum. Mol. Genet.22, 4136–4147 (2013). CASPubMed Google Scholar
Murakami, T. et al. ALS/FTD mutation-induced phase transition of FUS liquid droplets and reversible hydrogels into irreversible hydrogels impairs RNP granule function. Neuron88, 678–690 (2015). CASPubMedPubMed Central Google Scholar
Patel, A. et al. A liquid-to-solid phase transition of the ALS protein FUS accelerated by disease mutation. Cell162, 1066–1077 (2015). CASPubMed Google Scholar
Guo, L. et al. Nuclear-import receptors reverse aberrant phase transitions of RNA-binding proteins with prion-like domains. Cell173, 677–692 (2018). CASPubMedPubMed Central Google Scholar
Arnold, E. S. et al. ALS-linked TDP-43 mutations produce aberrant RNA splicing and adult-onset motor neuron disease without aggregation or loss of nuclear TDP-43. Proc. Natl Acad. Sci. USA110, E736–E745 (2013). CASPubMedPubMed Central Google Scholar
Kawahara, Y. & Mieda-Sato, A. TDP-43 promotes microRNA biogenesis as a component of the Drosha and Dicer complexes. Proc. Natl Acad. Sci. USA109, 3347–3352 (2012). CASPubMedPubMed Central Google Scholar
Coyne, A. N. et al. Fragile X protein mitigates TDP-43 toxicity by remodeling RNA granules and restoring translation. Hum. Mol. Genet.24, 6886–6898 (2015). CASPubMedPubMed Central Google Scholar
Alami, N. H. et al. Axonal transport of TDP-43 mRNA granules is impaired by ALS-causing mutations. Neuron81, 536–543 (2014). CASPubMedPubMed Central Google Scholar
Wang, I. F., Wu, L. S., Chang, H. Y. & Shen, C. K. TDP-43, the signature protein of FTLD-U, is a neuronal activity-responsive factor. J. Neurochem.105, 797–806 (2008). CASPubMed Google Scholar
Liao, Y.-C. et al. RNA granules hitchhike on lysosomes for long-distance transport, using annexin A11 as a molecular tether. Preprint at SSRNhttps://ssrn.com/abstract=3312723 (2019).
Kanai, Y., Dohmae, N. & Hirokawa, N. Kinesin transports RNA: isolation and characterization of an RNA-transporting granule. Neuron43, 513–525 (2004). CASPubMed Google Scholar
Fujii, R. & Takumi, T. TLS facilitates transport of mRNA encoding an actin-stabilizing protein to dendritic spines. J. Cell Sci.118, 5755–5765 (2005). CASPubMed Google Scholar
Lopez-Erauskin, J. et al. ALS/FTD-linked mutation in FUS suppresses intra-axonal protein synthesis and drives disease without nuclear loss-of-function of FUS. Neuron100, 816–830 (2018). CASPubMedPubMed Central Google Scholar
Qamar, S. et al. FUS phase separation is modulated by a molecular chaperone and methylation of arginine cation-pi interactions. Cell173, 720–734 (2018). CASPubMedPubMed Central Google Scholar
Buratti, E. & Baralle, F. E. Characterization and functional implications of the RNA binding properties of nuclear factor TDP-43, a novel splicing regulator of CFTR exon 9. J. Biol. Chem.276, 36337–36343 (2001). CASPubMed Google Scholar
Hallier, M., Lerga, A., Barnache, S., Tavitian, A. & Moreau-Gachelin, F. The transcription factor Spi-1/PU.1 interacts with the potential splicing factor TLS. J. Biol. Chem.273, 4838–4842 (1998). CASPubMed Google Scholar
Tollervey, J. R. et al. Characterizing the RNA targets and position-dependent splicing regulation by TDP-43. Nat. Neurosci.14, 452–458 (2011). CASPubMedPubMed Central Google Scholar
Polymenidou, M. et al. Long pre-mRNA depletion and RNA missplicing contribute to neuronal vulnerability from loss of TDP-43. Nat. Neurosci.14, 459–468 (2011). CASPubMedPubMed Central Google Scholar
Lagier-Tourenne, C. et al. Divergent roles of ALS-linked proteins FUS/TLS and TDP-43 intersect in processing long pre-mRNAs. Nat. Neurosci.15, 1488–1497 (2012). CASPubMedPubMed Central Google Scholar
Huelga, S. C. et al. Integrative genome-wide analysis reveals cooperative regulation of alternative splicing by hnRNP proteins. Cell Rep.1, 167–178 (2012). CASPubMedPubMed Central Google Scholar
Strong, M. J. et al. TDP43 is a human low molecular weight neurofilament (hNFL) mRNA-binding protein. Mol. Cell Neurosci.35, 320–327 (2007). CASPubMed Google Scholar
Costessi, L., Porro, F., Iaconcig, A. & Muro, A. F. TDP-43 regulates beta-adducin (Add2) transcript stability. RNA Biol.11, 1280–1290 (2014). PubMed Google Scholar
Colombrita, C. et al. TDP-43 and FUS RNA-binding proteins bind distinct sets of cytoplasmic messenger RNAs and differently regulate their post-transcriptional fate in motoneuron-like cells. J. Biol. Chem.287, 15635–15647 (2012). CASPubMedPubMed Central Google Scholar
Ling, J. P., Pletnikova, O., Troncoso, J. C. & Wong, P. C. TDP-43 repression of nonconserved cryptic exons is compromised in ALS-FTD. Science349, 650–655 (2015). CASPubMedPubMed Central Google Scholar
Schwartz, J. C. et al. FUS binds the CTD of RNA polymerase II and regulates its phosphorylation at Ser2. Genes Dev.26, 2690–2695 (2012). CASPubMedPubMed Central Google Scholar
Zhou, Y., Liu, S., Liu, G., Ozturk, A. & Hicks, G. G. ALS-associated FUS mutations result in compromised FUS alternative splicing and autoregulation. PLOS Genet.9, e1003895 (2013). PubMedPubMed Central Google Scholar
Guerrero, E. N. et al. TDP-43/FUS in motor neuron disease: complexity and challenges. Prog. Neurobiol.145–146, 78–97 (2016). PubMedPubMed Central Google Scholar
Velazquez-Perez, L. C., Rodriguez-Labrada, R. & Fernandez-Ruiz, J. Spinocerebellar ataxia type 2: clinicogenetic aspects, mechanistic insights, and management approaches. Front. Neurol.8, 472 (2017). PubMedPubMed Central Google Scholar
Becker, L. A. et al. Therapeutic reduction of ataxin-2 extends lifespan and reduces pathology in TDP-43 mice. Nature544, 367–371 (2017). CASPubMedPubMed Central Google Scholar
Lee, K. H. et al. C9orf72 dipeptide repeats impair the assembly, dynamics, and function of membrane-less organelles. Cell167, 774–788 (2016). CASPubMedPubMed Central Google Scholar
Bakthavachalu, B. et al. RNP-granule assembly via ataxin-2 disordered domains is required for long-term memory and neurodegeneration. Neuron98, 754–766 (2018). CASPubMed Google Scholar
Nonhoff, U. et al. Ataxin-2 interacts with the DEAD/H-box RNA helicase DDX6 and interferes with P-bodies and stress granules. Mol. Biol. Cell18, 1385–1396 (2007). CASPubMedPubMed Central Google Scholar
Johnson, J. O. et al. Exome sequencing reveals VCP mutations as a cause of familial ALS. Neuron68, 857–864 (2010). CASPubMedPubMed Central Google Scholar
Fecto, F. et al. SQSTM1 mutations in familial and sporadic amyotrophic lateral sclerosis. Arch. Neurol.68, 1440–1446 (2011). PubMed Google Scholar
Wu, C. H. et al. Mutations in the profilin 1 gene cause familial amyotrophic lateral sclerosis. Nature488, 499–503 (2012). CASPubMedPubMed Central Google Scholar
DeJesus-Hernandez, M. et al. Expanded GGGGCC hexanucleotide repeat in noncoding region of C9orf72 causes chromosome 9p-linked FTD and ALS. Neuron72, 245–256 (2011). CASPubMedPubMed Central Google Scholar
Renton, A. E. et al. A hexanucleotide repeat expansion in C9orf72 is the cause of chromosome 9p21-linked ALS-FTD. Neuron72, 257–268 (2011). CASPubMedPubMed Central Google Scholar
Freischmidt, A. et al. Haploinsufficiency of TBK1 causes familial ALS and fronto-temporal dementia. Nat. Neurosci.18, 631–636 (2015). CASPubMed Google Scholar
Bannwarth, S. et al. A mitochondrial origin for frontotemporal dementia and amyotrophic lateral sclerosis through CHCHD10 involvement. Brain137, 2329–2345 (2014). PubMedPubMed Central Google Scholar
Smith, B. N. et al. Exome-wide rare variant analysis identifies TUBA4A mutations associated with familial ALS. Neuron84, 324–331 (2014). CASPubMedPubMed Central Google Scholar
Puls, I. et al. Mutant dynactin in motor neuron disease. Nat. Genet.33, 455–456 (2003). CASPubMed Google Scholar
Greenway, M. J. et al. ANG mutations segregate with familial and ‘sporadic’ amyotrophic lateral sclerosis. Nat. Genet.38, 411–413 (2006). CASPubMed Google Scholar
Chen, Y. Z. et al. DNA/RNA helicase gene mutations in a form of juvenile amyotrophic lateral sclerosis (ALS4). Am. J. Hum. Genet.74, 1128–1135 (2004). CASPubMedPubMed Central Google Scholar
Kaneb, H. M. et al. Deleterious mutations in the essential mRNA metabolism factor, hGle1, in amyotrophic lateral sclerosis. Hum. Mol. Genet.24, 1363–1373 (2015). CASPubMed Google Scholar
Buchan, J. R., Kolaitis, R. M., Taylor, J. P. & Parker, R. Eukaryotic stress granules are cleared by autophagy and Cdc48/VCP function. Cell153, 1461–1474 (2013). CASPubMedPubMed Central Google Scholar
Matus, S., Bosco, D. A. & Hetz, C. Autophagy meets fused in sarcoma-positive stress granules. Neurobiol. Aging35, 2832–2835 (2014). CASPubMedPubMed Central Google Scholar
Dao, T. P. et al. Ubiquitin modulates liquid-liquid phase separation of UBQLN2 via disruption of multivalent interactions. Mol. Cell69, 965–978 (2018). CASPubMedPubMed Central Google Scholar
Monahan, Z., Shewmaker, F. & Pandey, U. B. Stress granules at the intersection of autophagy and ALS. Brain Res.1649, 189–200 (2016). CASPubMedPubMed Central Google Scholar
Thomas, M., Alegre-Abarrategui, J. & Wade-Martins, R. RNA dysfunction and aggrephagy at the centre of an amyotrophic lateral sclerosis/frontotemporal dementia disease continuum. Brain136, 1345–1360 (2013). PubMed Google Scholar
Ash, P. E. et al. Unconventional translation of C9orf72 GGGGCC expansion generates insoluble polypeptides specific to c9FTD/ALS. Neuron77, 639–646 (2013). CASPubMedPubMed Central Google Scholar
Mann, D. M. et al. Dipeptide repeat proteins are present in the p62 positive inclusions in patients with frontotemporal lobar degeneration and motor neurone disease associated with expansions in C9orf72. Acta Neuropathol. Commun.1, 68 (2013). PubMedPubMed Central Google Scholar
Mori, K. et al. hnRNP A3 binds to GGGGCC repeats and is a constituent of p62-positive/TDP43-negative inclusions in the hippocampus of patients with C9orf72 mutations. Acta Neuropathol.125, 413–423 (2013). CASPubMed Google Scholar
Mori, K. et al. The C9orf72 GGGGCC repeat is translated into aggregating dipeptide-repeat proteins in FTLD/ALS. Science339, 1335–1338 (2013). CASPubMed Google Scholar
Schludi, M. H. et al. Distribution of dipeptide repeat proteins in cellular models and C9orf72 mutation cases suggests link to transcriptional silencing. Acta Neuropathol.130, 537–555 (2015). CASPubMedPubMed Central Google Scholar
Zu, T. et al. Non-ATG-initiated translation directed by microsatellite expansions. Proc. Natl Acad. Sci. USA108, 260–265 (2011). CASPubMed Google Scholar
Gendron, T. F. et al. Antisense transcripts of the expanded C9orf72 hexanucleotide repeat form nuclear RNA foci and undergo repeat-associated non-ATG translation in c9FTD/ALS. Acta Neuropathol.126, 829–844 (2013). CASPubMedPubMed Central Google Scholar
Mackenzie, I. R. et al. Dipeptide repeat protein pathology in C9orf72 mutation cases: clinico-pathological correlations. Acta Neuropathol.126, 859–879 (2013). CASPubMed Google Scholar
Zu, T. et al. RAN proteins and RNA foci from antisense transcripts in C9orf72 ALS and frontotemporal dementia. Proc. Natl Acad. Sci. USA110, E4968–E4977 (2013). CASPubMedPubMed Central Google Scholar
Todd, P. K. et al. CGG repeat-associated translation mediates neurodegeneration in fragile X tremor ataxia syndrome. Neuron78, 440–455 (2013). CASPubMed Google Scholar
Lin, Y. et al. Toxic PR poly-dipeptides encoded by the C9orf72 repeat expansion target LC domain polymers. Cell167, 789–802 (2016). CASPubMedPubMed Central Google Scholar
Kwon, I. et al. Poly-dipeptides encoded by the C9orf72 repeats bind nucleoli, impede RNA biogenesis, and kill cells. Science345, 1139–1145 (2014). CASPubMedPubMed Central Google Scholar
Wen, X. et al. Antisense proline-arginine RAN dipeptides linked to C9orf72-ALS/FTD form toxic nuclear aggregates that initiate in vitro and in vivo neuronal death. Neuron84, 1213–1225 (2014). CASPubMedPubMed Central Google Scholar
Freibaum, B. D. et al. GGGGCC repeat expansion in C9orf72 compromises nucleocytoplasmic transport. Nature525, 129–133 (2015). CASPubMedPubMed Central Google Scholar
Mizielinska, S. et al. C9orf72 repeat expansions cause neurodegeneration in Drosophila through arginine-rich proteins. Science345, 1192–1194 (2014). CASPubMedPubMed Central Google Scholar
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). CASPubMedPubMed Central Google Scholar
Prudencio, M. et al. Distinct brain transcriptome profiles in C9orf72-associated and sporadic ALS. Nat. Neurosci.18, 1175–1182 (2015). CASPubMedPubMed Central Google Scholar
Jovicic, A. et al. Modifiers of C9orf72 dipeptide repeat toxicity connect nucleocytoplasmic transport defects to FTD/ALS. Nat. Neurosci.18, 1226–1229 (2015). CASPubMedPubMed Central Google Scholar
Burguete, A. S. et al. GGGGCC microsatellite RNA is neuritically localized, induces branching defects, and perturbs transport granule function. eLife4, e08881 (2015). PubMedPubMed Central Google Scholar
Shi, K. Y. et al. Toxic PRn poly-dipeptides encoded by the C9orf72 repeat expansion block nuclear import and export. Proc. Natl Acad. Sci. USA114, E1111–E1117 (2017). CASPubMedPubMed Central Google Scholar
Boeynaems, S. et al. Phase separation of C9orf72 dipeptide repeats perturbs stress granule dynamics. Mol. Cell65, 1044–1055 (2017). CASPubMedPubMed Central Google Scholar
Taneja, K. L., McCurrach, M., Schalling, M., Housman, D. & Singer, R. H. Foci of trinucleotide repeat transcripts in nuclei of myotonic dystrophy cells and tissues. J. Cell Biol.128, 995–1002 (1995). CASPubMed Google Scholar
Zhang, N. & Ashizawa, T. RNA toxicity and foci formation in microsatellite expansion diseases. Curr. Opin. Genet. Dev.44, 17–29 (2017). CASPubMedPubMed Central Google Scholar
Maharana, S. et al. RNA buffers the phase separation behavior of prion-like RNA binding proteins. Science360, 918–921 (2018). CASPubMedPubMed Central Google Scholar
Van Treeck, B. et al. RNA self-assembly contributes to stress granule formation and defining the stress granule transcriptome. Proc. Natl Acad. Sci. USA115, 2734–2739 (2018). PubMedPubMed Central Google Scholar
Khong, A. et al. The stress granule transcriptome reveals principles of mRNA accumulation in stress granules. Mol. Cell68, 808–820 (2017). CASPubMedPubMed Central Google Scholar
Lee, Y. B. et al. Hexanucleotide repeats in ALS/FTD form length-dependent RNA foci, sequester RNA binding proteins, and are neurotoxic. Cell Rep.5, 1178–1186 (2013). CASPubMedPubMed Central Google Scholar
Wang, E. T. et al. Transcriptome-wide regulation of pre-mRNA splicing and mRNA localization by muscleblind proteins. Cell150, 710–724 (2012). CASPubMedPubMed Central Google Scholar
Wojtkowiak-Szlachcic, A. et al. Short antisense-locked nucleic acids (all-LNAs) correct alternative splicing abnormalities in myotonic dystrophy. Nucleic Acids Res.43, 3318–3331 (2015). CASPubMedPubMed Central Google Scholar
Fratta, P. et al. C9orf72 hexanucleotide repeat associated with amyotrophic lateral sclerosis and frontotemporal dementia forms RNA G-quadruplexes. Sci. Rep.2, 1016 (2012). PubMedPubMed Central Google Scholar
Haeusler, A. R. et al. C9orf72 nucleotide repeat structures initiate molecular cascades of disease. Nature507, 195–200 (2014). CASPubMedPubMed Central Google Scholar
Sareen, D. et al. Targeting RNA foci in iPSC-derived motor neurons from ALS patients with a C9orf72 repeat expansion. Sci. Transl Med.5, 208ra149 (2013). PubMedPubMed Central Google Scholar
Donnelly, C. J. et al. RNA toxicity from the ALS/FTD C9orf72 expansion is mitigated by antisense intervention. Neuron80, 415–428 (2013). CASPubMedPubMed Central Google Scholar
Xu, Z. et al. Expanded GGGGCC repeat RNA associated with amyotrophic lateral sclerosis and frontotemporal dementia causes neurodegeneration. Proc. Natl Acad. Sci. USA110, 7778–7783 (2013). CASPubMedPubMed Central Google Scholar
Kim, H. J. & Taylor, J. P. Lost in transportation: nucleocytoplasmic transport defects in ALS and other neurodegenerative diseases. Neuron96, 285–297 (2017). CASPubMedPubMed Central Google Scholar
Nousiainen, H. O. et al. Mutations in mRNA export mediator GLE1 result in a fetal motoneuron disease. Nat. Genet.40, 155–157 (2008). CASPubMedPubMed Central Google Scholar
Gasset-Rosa, F. et al. Polyglutamine-expanded huntingtin exacerbates age-related disruption of nuclear integrity and nucleocytoplasmic transport. Neuron94, 48–57 (2017). CASPubMedPubMed Central Google Scholar
Hernandez-Vega, A. et al. Local nucleation of microtubule bundles through tubulin concentration into a condensed tau phase. Cell Rep.20, 2304–2312 (2017). CASPubMedPubMed Central Google Scholar
Wegmann, S. et al. Tau protein liquid-liquid phase separation can initiate tau aggregation. EMBO J.37, e98049 (2018). PubMedPubMed Central Google Scholar
Ambadipudi, S., Biernat, J., Riedel, D., Mandelkow, E. & Zweckstetter, M. Liquid-liquid phase separation of the microtubule-binding repeats of the Alzheimer-related protein Tau. Nat. Commun.8, 275 (2017). PubMedPubMed Central Google Scholar
Ferreon, J. C. et al. Acetylation disfavors tau phase separation. Int. J. Mol. Sci.19, E1360 (2018). PubMed Google Scholar
Kostylev, M. A. et al. Liquid and hydrogel phases of PrPC linked to conformation shifts and triggered by Alzheimer’s amyloid-beta oligomers. Mol. Cell72, 426–443 (2018). CASPubMedPubMed Central Google Scholar
Anderson, P. & Kedersha, N. Stress granules: the Tao of RNA triage. Trends Biochem. Sci.33, 141–150 (2008). CASPubMed Google Scholar
Decker, C. J. & Parker, R. P-Bodies and stress granules: possible roles in the control of translation and mRNA degradation. Cold Spring Harb. Perspect. Biol.4, a012286 (2012). PubMedPubMed Central Google Scholar
Ramaswami, M., Taylor, J. P. & Parker, R. Altered ribostasis: RNA-protein granules in degenerative disorders. Cell154, 727–736 (2013). CASPubMed Google Scholar
Kedersha, N. et al. Stress granules and processing bodies are dynamically linked sites of mRNP remodeling. J. Cell Biol.169, 871–884 (2005). CASPubMedPubMed Central Google Scholar
Hoyle, N. P., Castelli, L. M., Campbell, S. G., Holmes, L. E. & Ashe, M. P. Stress-dependent relocalization of translationally primed mRNPs to cytoplasmic granules that are kinetically and spatially distinct from P-bodies. J. Cell Biol.179, 65–74 (2007). CASPubMedPubMed Central Google Scholar
Parker, R. & Sheth, U. P bodies and the control of mRNA translation and degradation. Mol. Cell25, 635–646 (2007). CASPubMed Google Scholar
Wilczynska, A., Aigueperse, C., Kress, M., Dautry, F. & Weil, D. The translational regulator CPEB1 provides a link between DCP1 bodies and stress granules. J. Cell Sci.118, 981–992 (2005). CASPubMed Google Scholar
Mahboubi, H. & Stochaj, U. Nucleoli and stress granules: connecting distant relatives. Traffic15, 1179–1193 (2014). CASPubMed Google Scholar
Trinkle-Mulcahy, L. & Sleeman, J. E. The Cajal body and the nucleolus: “in a relationship” or “it’s complicated”? RNA Biol.14, 739–751 (2017). PubMed Google Scholar
Hofweber, M. et al. Phase separation of FUS is suppressed by its nuclear import receptor and arginine methylation. Cell173, 706–719 (2018). CASPubMed Google Scholar
Wiltzius, J. J. et al. Molecular mechanisms for protein-encoded inheritance. Nat. Struct. Mol. Biol.16, 973–978 (2009). CASPubMedPubMed Central Google Scholar