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Cited by 51Protein Kinase Regulation and GTPase SignalingAlzheimer's disease research and treatmentsNeuroscience and Neuropharmacology Research

Pharmacological Modulators of Small GTPases of Rho Family in Neurodegenerative Diseases

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Guiler, William, Koehler, Addison, Boykin, Christi, Lu, Qun·2021·Frontiers in Cellular Neuroscience
DOI 10.3389/fncel.2021.661612PMC PMC8149604
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Abstract

Classical Rho GTPases, including RhoA, Rac1, and Cdc42, are members of the Ras small GTPase superfamily and play essential roles in a variety of cellular functions. Rho GTPase signaling can be turned on and off by specific GEFs and GAPs, respectively. These features empower Rho GTPases and their upstream and downstream modulators as targets for scientific research and therapeutic intervention. Specifically, significant therapeutic potential exists for targeting Rho GTPases in neurodegenerative diseases due to their widespread cellular activity and alterations in neural tissues. This study will explore the roles of Rho GTPases in neurodegenerative diseases with focus on the applications of pharmacological modulators in recent discoveries. There have been exciting developments of small molecules, nonsteroidal anti-inflammatory drugs (NSAIDs), and natural products and toxins for each classical Rho GTPase category. A brief overview of each category followed by examples in their applications will be provided. The literature on their roles in various diseases [e.g., Alzheimer’s disease (AD), Parkinson’s disease (PD), Amyotrophic lateral sclerosis (ALS), Frontotemporal dementia (FTD), and Multiple sclerosis (MS)] highlights the unique and broad implications targeting Rho GTPases for potential therapeutic intervention. Clearly, there is increasing knowledge of therapeutic promise from the discovery of pharmacological modulators of Rho GTPases for managing and treating these conditions. The progress is also accompanied by the recognition of complex Rho GTPase modulation where targeting its signaling can improve some aspects of pathogenesis while exacerbating others in the same disease model. Future directions should emphasize the importance of elucidating how different Rho GTPases work in concert and how they produce such widespread yet different cellular responses during neurodegenerative disease progression.

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  • RhoA and many of its downstream effector proteins are highly expressed in the nervous system, implying an important role for RhoA signaling in neurons and glial cells.

    “RhoA and many of its downstream effector proteins are highly expressed in the nervous system, implying an important role for RhoA signaling in neurons and glial cells.”

    From RhoA Signaling in Neurodegenerative Diseases (2022) · cites this paper as [117]

    The Introduction’s “Rho GTPase Subfamily” section describes RhoA’s effects on neuronal processes and reports that loss of RhoA in microglia led to synapse loss in mice. The “Small Molecules” section says the RhoA effector ROCK2 is mainly expressed in the brain and spinal cord. Neither passage establishes that RhoA and many of its downstream effectors are highly expressed throughout the nervous system; no page numbers are available in our copy. (LLM, conf=0.86)

    Experimental — accuracy not yet measured

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Research works printed but not linked: 170

  1. Aguilar B. J. Zhao Y. Zhou H. Huo S. Chen Y.-H. Lu Q. (2019). Inhibition of Cdc42-intersectin interaction by small molecule ZCL367 impedes cancer cell cycle progression, proliferation, migration and tumor growth. Cancer Biol. Ther. 20, 740– 749. 10.1080/15384047.2018.1564559 30849276 PMC6606017 · DOI
  2. Aguilar B. J. Zhou H. Lu Q. (2017a). Cdc42 signaling pathway Inhibition as a therapeutic target in ras- related cancers. Curr. Med. Chem. 24, 3485– 3507. 10.2174/0929867324666170602082956 28571533 · DOI
  3. Aguilar B. J. Zhu Y. Lu Q. (2017b). Rho GTPases as therapeutic targets in Alzheimer’s disease. Alzheimers Res. Ther. 9: 97. 10.1186/s13195-017-0320-4 29246246 PMC5732365 · DOI
  4. Ahmed L. A. Darwish H. A. Abdelsalam R. M. Amin H. A. (2016). Role of Rho kinase Inhibition in the protective effect of fasudil and simvastatin against 3-nitropropionic acid-induced striatal neurodegeneration and mitochondrial dysfunction in rats. Mol. Neurobiol. 53, 3927– 3938. 10.1007/s12035-015-9303-2 26169112 · DOI · Paper page
  5. Arrazola Sastre A. Luque Montoro M. Gálvez-Martín P. Lacerda H. M. Lucia A. M. Llavero F.. (2020). Small GTPases of the Ras and Rho families switch on/off signaling pathways in neurodegenerative diseases. Int. J. Mol. Sci. 21: 6312. 10.3390/ijms21176312 32878220 PMC7504559 · DOI · Paper page
  6. Auer M. Hausott B. Klimaschewski L. (2011). Rho GTPases as regulators of morphological neuroplasticity. Ann. Anat. 193, 259– 266. 10.1016/j.aanat.2011.02.015 21459565 PMC3143277 · DOI
  7. Ba W. Nadif Kasri N. (2017). RhoGTPases at the synapse: an embarrassment of choice. Small GTPases 8, 106– 113. 10.1080/21541248.2016.1206352 27492682 PMC5464131 · DOI
  8. Bang J. Spina S. Miller B. L. (2015). Frontotemporal dementia. The Lancet 386, 1672– 1682. 10.1016/S0140-6736(15)00461-4 26595641 PMC5970949 · DOI · Paper page
  9. Barcia C. Ros C. M. Annese V. Carrillo-de Sauvage M. A. Ros-Bernal F. Gómez A.. (2012). ROCK/Cdc42-mediated microglial motility and gliapse formation lead to phagocytosis of degenerating dopaminergic neurons in vivo. Sci. Rep. 2: 809. 10.1038/srep00809 23139861 PMC3492875 · DOI · Paper page
  10. Beljan S. Herak Bosnar M. Ćetković H. (2020). Rho family of ras-like gtpases in early-branching animals. Cells 9: 2279. 10.3390/cells9102279 33066017 PMC7600811 · DOI
  11. Bito H. Furuyashiki T. Ishihara H. Shibasaki Y. Ohashi K. Mizuno K.. (2000). A critical role for a Rho-associated kinase, p160ROCK, in determining axon outgrowth in mammalian CNS neurons. Neuron 26, 431– 441. 10.1016/s0896-6273(00)81175-7 10839361 · DOI
  12. Bolognin S. Lorenzetto E. Diana G. Buffelli M. (2014). The potential role of rho GTPases in Alzheimer’s disease pathogenesis. Mol. Neurobiol. 50, 406– 422. 10.1007/s12035-014-8637-5 24452387 · DOI
  13. Borin M. Saraceno C. Catania M. Lorenzetto E. Pontelli V. Paterlini A.. (2018). Rac1 activation links tau hyperphosphorylation and Aβ dysmetabolism in Alzheimer’s disease. Acta Neuropathol. Commun. 6: 61. 10.1186/s40478-018-0567-4 30005699 PMC6045891 · DOI · Paper page
  14. Bowerman M. Beauvais A. Anderson C. L. Kothary R. (2010). Rho-kinase inactivation prolongs survival of an intermediate SMA mouse model. Hum. Mol. Genet. 19, 1468– 1478. 10.1093/hmg/ddq021 20097679 · DOI
  15. Bowerman M. Murray L. M. Beauvais A. Pinheiro B. Kothary R. (2012). A critical smn threshold in mice dictates onset of an intermediate spinal muscular atrophy phenotype associated with a distinct neuromuscular junction pathology. Neuromuscul. Disord 22, 263– 276. 10.1016/j.nmd.2011.09.007 22071333 · DOI
  16. Boykin C. Zhang G. Chen Y.-H. Zhang R.-W. Fan X.-E. Yang W.-M.. (2011). Cucurbitacin IIa: a novel class of anti-cancer drug inducing non-reversible actin aggregation and inhibiting survivin independent of JAK2/STAT3 phosphorylation. Br. J. Cancer 104, 781– 789. 10.1038/bjc.2011.10 21304528 PMC3048206 · DOI
  17. Breitenlechner C. Gassel M. Hidaka H. Kinzel V. Huber R. Engh R. A.. (2003). Protein kinase A in complex with Rho-kinase inhibitors Y-27632, Fasudil and H-1152P: structural basis of selectivity. Struct. 11, 1595– 1607. 10.1016/j.str.2003.11.002 14656443 · DOI
  18. Cao X. C. Pappalardo L. W. Waxman S. G. Tan A. M. (2017). Dendritic spine dysgenesis in superficial dorsal horn sensory neurons after spinal cord injury. Mol. Pain 13: 1744806916688016. 10.1177/1744806916688016 28326929 PMC5302173 · DOI
  19. Cardama G. A. Comin M. J. Hornos L. Gonzalez N. Defelipe L. Turjanski A. G.. (2014). Preclinical development of novel Rac1-GEF signaling inhibitors using a rational design approach in highly aggressive breast cancer cell lines. Anticancer Agents Med. Chem. 14, 840– 851. 10.2174/18715206113136660334 24066799 PMC4104455 · DOI
  20. Cerri C. Fabbri A. Vannini E. Spolidoro M. Costa M. Maffei L.. (2011). Activation of Rho GTPases triggers structural remodeling and functional plasticity in the adult rat visual cortex. J. Neurosci. 31, 15163– 15172. 10.1523/JNEUROSCI.2617-11.2011 22016550 PMC6623549 · DOI
  21. Chan D. Citro A. Cordy J. M. Shen G. C. Wolozin B. (2011). Rac1 protein rescues neurite retraction caused by G2019S leucine-rich repeat kinase 2 (LRRK2). J. Biol. Chem. 286, 16140– 16149. 10.1074/jbc.M111.234005 21454543 PMC3091223 · DOI
  22. Chen F. Ma L. Parrini M. C. Mao X. Lopez M. Wu C.. (2000). Cdc42 is required for PIP(2)-induced actin polymerization and early development but not for cell viability. Curr. Biol. 10, 758– 765. 10.1016/s0960-9822(00)00571-6 10898977 · DOI
  23. Chen S. Sun C. Wang H. Wang J. (2015). The role of Rho GTPases in toxicity of clostridium difficile toxins. Toxins 7, 5254– 5267. 10.3390/toxins7124874 26633511 PMC4690124 · DOI
  24. Ciurleo R. Bramanti P. Marino S. (2014). Role of statins in the treatment of multiple sclerosis. Pharmacol. Res. 87, 133– 143. 10.1016/j.phrs.2014.03.004 24657241 · DOI
  25. Clayton N. S. Ridley A. J. (2020). Targeting Rho GTPase signaling networks in cancer. Front. Cell Dev. Biol. 8: 222. 10.3389/fcell.2020.00222 32309283 PMC7145979 · DOI
  26. Coque E. Raoul C. Bowerman M. (2014). ROCK inhibition as a therapy for spinal muscular atrophy: understanding the repercussions on multiple cellular targets. Front. Neurosci. 8: 271. 10.3389/fnins.2014.00271 25221469 PMC4148024 · DOI
  27. Cordle A. Landreth G. (2005). 3-Hydroxy-3-methylglutaryl-coenzyme A reductase inhibitors attenuate beta-amyloid-induced microglial inflammatory responses. J. Neurosci. 25, 299– 307. 10.1523/JNEUROSCI.2544-04.2005 15647473 PMC6725473 · DOI
  28. Couch B. A. DeMarco G. J. Gourley S. L. Koleske A. J. (2010). Increased dendrite branching in AbetaPP/PS1 mice and elongation of dendrite arbors by fasudil administration. J. Alzheimers Dis. 20, 1003– 1008. 10.3233/JAD-2010-091114 20413901 PMC3077946 · DOI
  29. D’Ambrosi N. Rossi S. Gerbino V. Cozzolino M. (2014). Rac1 at the crossroad of actin dynamics and neuroinflammation in Amyotrophic Lateral Sclerosis. Front. Cell. Neurosci. 8: 279. 10.3389/fncel.2014.00279 25249940 PMC4157560 · DOI
  30. Davies S. P. Reddy H. Caivano M. Cohen P. (2000). Specificity and mechanism of action of some commonly used protein kinase inhibitors. Biochem. J. 351, 95– 105. 10.1042/0264-6021:3510095 10998351 PMC1221339 · DOI
  31. Désiré L. Bourdin J. Loiseau N. Peillon H. Picard V. De Oliveira C.. (2005). RAC1 inhibition targets amyloid precursor protein processing by gamma-secretase and decreases Abeta production in vitro and in vivo. J. Biol. Chem. 280, 37516– 37525. 10.3760/cma.j.cn112137-20210110-00068 16150730 · DOI
  32. Diana G. Valentini G. Travaglione S. Falzano L. Pieri M. Zona C.. (2007). Enhancement of learning and memory after activation of cerebral Rho GTPases. Proc. Natl. Acad. Sci. U S A 104, 636– 641. 10.1073/pnas.0610059104 17202256 PMC1761909 · DOI
  33. Dill J. Patel A. R. Yang X.-L. Bachoo R. Powell C. M. Li S. (2010). A molecular mechanism for ibuprofen-mediated RhoA inhibition in neurons. J. Neurosci. 30, 963– 972. 10.1523/JNEUROSCI.5045-09.2010 20089905 PMC3904382 · DOI
  34. Dols-Icardo O. García-Redondo A. Rojas-García R. Sánchez-Valle R. Noguera A. Gómez-Tortosa E.. (2014). Characterization of the repeat expansion size in C9orf72 in amyotrophic lateral sclerosis and frontotemporal dementia. Hum. Mol. Genet. 23, 749– 754. 10.1093/hmg/ddt460 24057670 · DOI
  35. Elshaer S. L. Alwhaibi A. Mohamed R. Lemtalsi T. Coucha M. Longo F. M.. (2019). Modulation of the p75 neurotrophin receptor using LM11A-31 prevents diabetes-induced retinal vascular permeability in mice via inhibition of inflammation and the RhoA kinase pathway. Diabetologia 62, 1488– 1500. 10.1007/s00125-019-4885-2 31073629 PMC8808141 · DOI
  36. Feng Y. LoGrasso P. V. Defert O. Li R. (2016). Rho kinase (ROCK) Inhibitors and their therapeutic potential. J. Med. Chem. 59, 2269– 2300. 10.1021/acs.jmedchem.5b00683 26486225 · DOI
  37. Feng Y. Yin Y. Weiser A. Griffin E. Cameron M. D. Lin L.. (2008). Discovery of substituted 4-(pyrazol-4-yl)-phenylbenzodioxane-2-carboxamides as potent and highly selective Rho kinase (ROCK-II) inhibitors. J. Med. Chem. 51, 6642– 6645. 10.1021/jm800986w 18834107 PMC3708311 · DOI
  38. Ferrera P. Zepeda A. Arias C. (2017). Nonsteroidal anti-inflammatory drugs attenuate amyloid-β protein-induced actin cytoskeletal reorganization through Rho signaling modulation. Cell. Mol. Neurobiol. 37, 1311– 1318. 10.1007/s10571-017-0467-3 28124209 PMC11482099 · DOI
  39. Ferri N. Corsini A. Bottino P. Clerici F. Contini A. (2009). Virtual screening approach for the identification of new Rac1 inhibitors. J. Med. Chem. 52, 4087– 4090. 10.1021/jm8015987 19527032 · DOI
  40. Figueiredo-Pereira M. E. Corwin C. Babich J. (2016). Prostaglandin J2: a potential target for halting inflammation-induced neurodegeneration. Ann. N. Y. Acad. Sci. 1363, 125– 137. 10.1111/nyas.12987 26748744 PMC4801700 · DOI
  41. Fink H. A. Jutkowitz E. McCarten J. R. Hemmy L. S. Butler M. Davila H.. (2018). Pharmacologic interventions to prevent cognitive decline, mild cognitive impairment and clinical Alzheimer-type dementia: a systematic review. Ann. Intern. Med. 168, 39– 51. 10.7326/M17-1529 29255847 · DOI
  42. Fransson A. Ruusala A. Aspenström P. (2003). Atypical Rho GTPases have roles in mitochondrial homeostasis and apoptosis. J. Biol. Chem. 278, 6495– 6502. 10.1074/jbc.M208609200 12482879 · DOI
  43. Friesland A. Zhao Y. Chen Y.-H. Wang L. Zhou H. Lu Q. (2013). Small molecule targeting Cdc42-intersectin interaction disrupts Golgi organization and suppresses cell motility. Proc. Natl. Acad. Sci. U S A 110, 1261– 1266. 10.1073/pnas.1116051110 23284167 PMC3557054 · DOI
  44. Fu P.-C. Tang R.-H. Yu Z.-Y. Xie M.-J. Wang W. Luo X. (2018). The Rho-associated kinase inhibitors Y27632 and fasudil promote microglial migration in the spinal cord via the ERK signaling pathway. Neural Regen. Res. 13, 677– 683. 10.4103/1673-5374.230294 29722320 PMC5950678 · DOI
  45. Galan-Rodriguez B. Martin E. Brouillet E. Déglon N. Betuing S. Caboche J. (2017). Coupling of D2R Short but not D2R Long receptor isoform to the Rho/ROCK signaling pathway renders striatal neurons vulnerable to mutant huntingtin. Eur. J. Neurosci. 45, 198– 206. 10.1111/ejn.13415 27717053 · DOI · Paper page
  46. Gao C. Huang L. Long Y. Zheng J. Yang J. Pu S.. (2013). Y-39983, a selective Rho-kinase inhibitor, attenuates experimental autoimmune encephalomyelitis via inhibition of demyelination. Neuroimmunomodulation 20, 334– 340. 10.1159/000353568 24008512 · DOI
  47. Gao Y. Dickerson J. B. Guo F. Zheng J. Zheng Y. (2004). Rational design and characterization of a Rac GTPase-specific small molecule inhibitor. Proc. Natl. Acad. Sci. U S A 101, 7618– 7623. 10.1073/pnas.0307512101 15128949 PMC419655 · DOI · Paper page
  48. Gärtner U. Holzer M. Arendt T. (1999). Elevated expression of p21ras is an early event in Alzheimer’s disease and precedes neurofibrillary degeneration. Neuroscience 91, 1– 5. 10.1016/s0306-4522(99)00059-7 10336054 · DOI
  49. Gebbink M. F. Kranenburg O. Poland M. van Horck F. P. Houssa B. Moolenaar W. H. (1997). Identification of a novel, putative Rho-specific GDP/GTP exchange factor and a RhoA-binding protein: control of neuronal morphology. J. Cell Biol. 137, 1603– 1613. 10.1083/jcb.137.7.1603 9199174 PMC2137826 · DOI
  50. Ghasemi M. Brown R. H. (2018). Genetics of Amyotrophic Lateral Sclerosis. Cold Spring Harb. Perspect. Med. 8. 10.1101/cshperspect.a024125 PMC5932579 28270533 · DOI
  51. Gray J. L. von Delft F. Brennan P. E. (2020). Targeting the Small GTPase superfamily through their regulatory proteins. Angew. Chem. Int. Ed Engl. 59, 6342– 6366. 10.1002/anie.201900585 30869179 PMC7204875 · DOI
  52. Gu Q.-F. Yu J.-Z. Wu H. Li Y.-H. Liu C.-Y. Feng L.. (2018). Therapeutic effect of Rho kinase inhibitor FSD-C10 in a mouse model of Alzheimer’s disease. Exp. Ther. Med. 16, 3929– 3938. 10.3892/etm.2018.6701 30344671 PMC6176147 · DOI · Paper page
  53. Hadano S. Hand C. K. Osuga H. Yanagisawa Y. Otomo A. Devon R. S.. (2001). A gene encoding a putative GTPase regulator is mutated in familial amyotrophic lateral sclerosis 2. Nat. Genet. 29, 166– 173. 10.1038/ng1001-166 11586298 · DOI
  54. Hall A. (2012). Rho family GTPases. Biochem. Soc. Trans. 40, 1378– 1382. 10.1042/BST20120103 23176484 · DOI
  55. Hamano T. Shirafuji N. Yen S.-H. Yoshida H. Kanaan N. M. Hayashi K.. (2020). Rho-kinase ROCK inhibitors reduce oligomeric tau protein. Neurobiol. Aging 89, 41– 54. 10.1016/j.neurobiolaging.2019.12.009 31982202 PMC7183001 · DOI · Paper page
  56. Harrington A. W. Li Q. M. Tep C. Park J. B. He Z. Yoon S. O. (2008). The role of Kalirin9 in p75/nogo receptor-mediated RhoA activation in cerebellar granule neurons. J. Biol. Chem. 283, 24690– 24697. 10.1074/jbc.M802188200 18625710 PMC2529002 · DOI
  57. Heasman S. J. Ridley A. J. (2008). Mammalian Rho GTPases: new insights into their functions from in vivo studies. Nat. Rev. Mol. Cell Biol. 9, 690– 701. 10.1038/nrm2476 18719708 · DOI · Paper page
  58. Hedrick N. G. Yasuda R. (2017). Regulation of Rho GTPase proteins during spine structural plasticity for the control of local dendritic plasticity. Curr. Opin. Neurobiol. 45, 193– 201. 10.1016/j.conb.2017.06.002 28709063 · DOI
  59. Herskowitz J. H. Feng Y. Mattheyses A. L. Hales C. M. Higginbotham L. A. Duong D. M.. (2013). Pharmacologic inhibition of ROCK2 suppresses amyloid-β production in an Alzheimer’s disease mouse model. J. Neurosci. 33, 19086– 19098. 10.1523/JNEUROSCI.2508-13.2013 24305806 PMC3850036 · DOI · Paper page
  60. Hsieh C.-H. Li L. Vanhauwaert R. Nguyen K. T. Davis M. D. Bu G.. (2019). Miro1 marks Parkinson’s disease subset and Miro1 reducer rescues neuron loss in Parkinson’s models. Cell Metab. 30, 1131– 1140.e7. 10.1016/j.cmet.2019.08.023 31564441 PMC6893131 · DOI
  61. Hsieh C.-H. Shaltouki A. Gonzalez A. E. Bettencourt da Cruz A. Burbulla L. F. St Lawrence E.. (2016). Functional impairment in miro degradation and mitophagy is a shared feature in familial and sporadic Parkinson’s disease. Cell Stem Cell 19, 709– 724. 10.1016/j.stem.2016.08.002 27618216 PMC5135570 · DOI
  62. Huesa G. Baltrons M. A. Gómez-Ramos P. Morán A. García A. Hidalgo J.. (2010). Altered distribution of RhoA in Alzheimer’s disease and AβPP overexpressing mice. J. Alzheimers Dis. 19, 37– 56. 10.3233/JAD-2010-1203 20061625 · DOI · Paper page
  63. Humphries-Bickley T. Castillo-Pichardo L. Hernandez-O’Farrill E. Borrero-Garcia L. D. Forestier-Roman I. Gerena Y.. (2017). Characterization of a dual Rac/Cdc42 inhibitor MBQ-167 in metastatic cancer. Mol. Cancer Ther. 16, 805– 818. 10.1158/1535-7163.MCT-16-0442 28450422 PMC5418092 · DOI
  64. Hunter M. P. Russo A. O’Bryan J. P. (2013). Emerging roles for intersectin (ITSN) in regulating signaling and disease pathways. Int. J. Mol. Sci. 14, 7829– 7852. 10.3390/ijms14047829 23574942 PMC3645719 · DOI
  65. Ikenoya M. Hidaka H. Hosoya T. Suzuki M. Yamamoto N. Sasaki Y. (2002). Inhibition of rho-kinase-induced myristoylated alanine-rich C kinase substrate (MARCKS) phosphorylation in human neuronal cells by H-1152, a novel and specific Rho-kinase inhibitor. J. Neurochem. 81, 9– 16. 10.1046/j.1471-4159.2002.00801.x 12067241 · DOI
  66. Ishizaki T. Uehata M. Tamechika I. Keel J. Nonomura K. Maekawa M.. (2000). Pharmacological properties of Y-27632, a specific inhibitor of rho-associated kinases. Mol. Pharmacol. 57, 976– 983. 10779382
  67. Iyer S. Subramanian V. Acharya K. R. (2018). C9orf72, a protein associated with amyotrophic lateral sclerosis (ALS) is a guanine nucleotide exchange factor. PeerJ 6: e5815. 10.7717/peerj.5815 30356970 PMC6195791 · DOI
  68. James S. E. Burden H. Burgess R. Xie Y. Yang T. Massa S. M.. (2008). Anti-cancer drug induced neurotoxicity and identification of Rho pathway signaling modulators as potential neuroprotectants. Neurotoxicology 29, 605– 612. 10.1016/j.neuro.2008.04.008 18539332 PMC2615238 · DOI
  69. Jones S. B. Lu H. Y. Lu Q. (2004). Abl tyrosine kinase promotes dendrogenesis by inducing actin cytoskeletal rearrangements in cooperation with Rho family small GTPases in hippocampal neurons. J. Neurosci. 24, 8510– 8521. 10.1523/JNEUROSCI.1264-04.2004 15456825 PMC6729913 · DOI
  70. Jordan F. Quinn T. J. McGuinness B. Passmore P. Kelly J. P. Tudur Smith C.. (2020). Aspirin and other non-steroidal anti-inflammatory drugs for the prevention of dementia. Cochrane Database Syst. Rev. 4: CD011459. 10.1002/14651858.CD011459.pub2 32352165 PMC7192366 · DOI
  71. Just I. Gerhard R. (2004). Large clostridial cytotoxins. Rev. Physiol. Biochem. Pharmacol. 152, 23– 47. 10.1007/s10254-004-0033-5 15449191 · DOI
  72. Kanekura K. Hashimoto Y. Niikura T. Aiso S. Matsuoka M. Nishimoto I. (2004). ALSin, the product of ALS2 gene, suppresses SOD1 mutant neurotoxicity through RhoGEF domain by interacting with SOD1 mutants. J. Biol. Chem. 279, 19247– 19256. 10.1074/jbc.M313236200 14970233 · DOI
  73. Kikuchi M. Sekiya M. Hara N. Miyashita A. Kuwano R. Ikeuchi T.. (2020). Disruption of a RAC1-centred network is associated with Alzheimer’s disease pathology and causes age-dependent neurodegeneration. Hum. Mol. Genet. 29, 817– 833. 10.1093/hmg/ddz320 31942999 PMC7191305 · DOI
  74. Kim H. Calatayud C. Guha S. Fernández-Carasa I. Berkowitz L. Carballo-Carbajal I.. (2018). The small GTPase RAC1/CED-10 is essential in maintaining dopaminergic neuron function and survival against α-synuclein-induced toxicity. Mol. Neurobiol. 55, 7533– 7552. 10.1007/s12035-018-0881-7 29429047 PMC6096980 · DOI
  75. Kim H. Han J.-R. Park J. Oh M. James S. E. Chang S.. (2008a). Delta-catenin-induced dendritic morphogenesis. An essential role of p190RhoGEF interaction through Akt1-mediated phosphorylation. J. Biol. Chem. 283, 977– 987. 10.1074/jbc.M707158200 17993462 PMC2265781 · DOI
  76. Kim H. Oh M. Lu Q. Kim K. (2008b). E-Cadherin negatively modulates delta-catenin-induced morphological changes and RhoA activity reduction by competing with p190RhoGEF for delta-catenin. Biochem. Biophys. Res. Commun. 377, 636– 641. 10.1016/j.bbrc.2008.10.030 18930028 PMC2614342 · DOI
  77. Koch J. C. Tatenhorst L. Roser A.-E. Saal K.-A. Tönges L. Lingor P. (2018). ROCK inhibition in models of neurodegeneration and its potential for clinical translation. Pharmacol. Ther. 189, 1– 21. 10.1016/j.pharmthera.2018.03.008 29621594 · DOI · Paper page
  78. Koch J. C. Tönges L. Barski E. Michel U. Bähr M. Lingor P. (2014). ROCK2 is a major regulator of axonal degeneration, neuronal death and axonal regeneration in the CNS. Cell Death Dis. 5:e1225. 10.1038/cddis.2014.191 24832597 PMC4047920 · DOI · Paper page
  79. Kopp M. A. Liebscher T. Niedeggen A. Laufer S. Brommer B. Jungehulsing G. J.. (2012). Small-molecule-induced Rho-inhibition: NSAIDs after spinal cord injury. Cell Tissue Res. 349, 119– 132. 10.1007/s00441-012-1334-7 22350947 PMC3744771 · DOI
  80. Lee S. J. Zdradzinski M. D. Sahoo P. K. Kar A. N. Patel P. Kawaguchi R.. (2021). Selective axonal translation of prenylated Cdc42 mRNA isoform supports axon growth. J. Cell Sci. 5: jcs.251967. 10.1242/jcs.251967 33674450 PMC8077440 · DOI
  81. Lee Y.-C. Cheng T.-H. Lee J.-S. Chen J.-H. Liao Y.-C. Fong Y.. (2011). Nobiletin, a citrus flavonoid, suppresses invasion and migration involving FAK/PI3K/Akt and small GTPase signals in human gastric adenocarcinoma AGS cells. Mol. Cell. Biochem. 347, 103– 115. 10.1007/s11010-010-0618-z 20963626 · DOI
  82. Leoni E. Bremang M. Mitra V. Zubiri I. Jung S. Lu C.-H.. (2019). Combined tissue-fluid proteomics to unravel phenotypic variability in amyotrophic lateral sclerosis. Sci. Rep. 9: 4478. 10.1038/s41598-019-40632-4 30872628 PMC6418138 · DOI
  83. Lerm M. Schmidt G. Aktories K. (2000). Bacterial protein toxins targeting rho GTPases. FEMS Microbiol. Lett. 188, 1– 6. 10.1111/j.1574-6968.2000.tb09159.x 10867225 · DOI
  84. Li Y. Xu J. Xu P. Song S. Liu P. Chi T.. (2016). Xanthoceras sorbifolia extracts ameliorate dendritic spine deficiency and cognitive decline via upregulation of BDNF expression in a rat model of Alzheimer’s disease. Neurosci. Lett. 629, 208– 214. 10.1016/j.neulet.2016.07.011 27412235 · DOI
  85. Li Y.-H. Xie C. Zhang Y. Li X. Zhang H.-F. Wang Q.. (2017). FSD-C10, a Fasudil derivative, promotes neuroregeneration through indirect and direct mechanisms. Sci. Rep. 7: 41227. 10.1038/srep41227 28112256 PMC5255566 · DOI
  86. Liu J. Gao H.-Y. Wang X.-F. (2015). The role of the Rho/ROCK signaling pathway in inhibiting axonal regeneration in the central nervous system. Neural Regen. Res. 10, 1892– 1896. 10.4103/1673-5374.170325 26807132 PMC4705809 · DOI
  87. Liu W. Du W. Shang X. Wang L. Evelyn C. Florian M. C.. (2019). Rational identification of a Cdc42 inhibitor presents a new regimen for long-term hematopoietic stem cell mobilization. Leukemia 33, 749– 761. 10.1038/s41375-018-0251-5 30254339 PMC6414073 · DOI
  88. Lu Q. Aguilar B. J. Li M. Jiang Y. Chen Y.-H. (2016). Genetic alterations of δ-catenin/NPRAP/Neurojungin (CTNND2): functional implications in complex human diseases. Hum. Genet. 135, 1107– 1116. 10.1007/s00439-016-1705-3 27380241 PMC5021578 · DOI
  89. Lu Q. Longo F. M. Zhou H. Massa S. M. Chen Y.-H. (2009). Signaling through Rho GTPase pathway as viable drug target. Curr. Med. Chem. 16, 1355– 1365. 10.2174/092986709787846569 19355891 PMC3829470 · DOI
  90. Luo L. Hensch T. K. Ackerman L. Barbel S. Jan L. Y. Jan Y. N. (1996). Differential effects of the Rac GTPase on Purkinje cell axons and dendritic trunks and spines. Nature 379, 837– 840. 10.1038/379837a0 8587609 · DOI
  91. Ma Y. Ma B. Shang Y. Yin Q. Hong Y. Xu S.. (2018). Flavonoid-rich ethanol extract from the leaves of Diospyros kaki attenuates cognitive deficits, amyloid-beta production, oxidative stress and neuroinflammation in APP/PS1 transgenic mice. Brain Res. 1678, 85– 93. 10.1016/j.brainres.2017.10.001 29038004 · DOI
  92. Manterola L. Hernando-Rodríguez M. Ruiz A. Apraiz A. Arrizabalaga O. Vellón L.. (2013). 1–42 β-amyloid peptide requires PDK1/nPKC/Rac 1 pathway to induce neuronal death. Transl. Psychiatry 3: e219. 10.1038/tp.2012.147 23340502 PMC3566727 · DOI
  93. Maroccia Z. Loizzo S. Travaglione S. Frank C. Fabbri A. Fiorentini C. (2018). New therapeutics from Nature: the odd case of the bacterial cytotoxic necrotizing factor 1. Biomed. Pharmacother. 101, 929– 937. 10.1016/j.biopha.2018.02.140 29635902 · DOI
  94. Martinez L. A. Tejada-Simon M. V. (2011). Pharmacological inactivation of the small GTPase Rac1 impairs long-term plasticity in the mouse hippocampus. Neuropharmacology 61, 305– 312. 10.1016/j.neuropharm.2011.04.017 21569781 PMC3106418 · DOI
  95. Martin-Vilchez S. Whitmore L. Asmussen H. Zareno J. Horwitz R. Newell-Litwa K. (2017). RhoGTPase regulators orchestrate distinct stages of synaptic development. PLoS One 12: e0170464. 10.1371/journal.pone.0170464 28114311 PMC5256999 · DOI
  96. Medina M. Marinescu R. C. Overhauser J. Kosik K. S. (2000). Hemizygosity of delta-catenin (CTNND2) is associated with severe mental retardation in cri-du-chat syndrome. Genomics 63, 157– 164. 10.1006/geno.1999.6090 10673328 · DOI
  97. Mendoza-Naranjo A. Contreras-Vallejos E. Henriquez D. R. Otth C. Bamburg J. R. Maccioni R. B.. (2012). Fibrillar amyloid-β1–42 modifies actin organization affecting the cofilin phosphorylation state: a role for Rac1/cdc42 effector proteins and the slingshot phosphatase. J. Alzheimers Dis. 29, 63– 77. 10.3233/JAD-2012-101575 22204905 · DOI
  98. Mendoza-Naranjo A. Gonzalez-Billault C. Maccioni R. B. (2007). Aβ1–42 stimulates actin polymerization in hippocampal neurons through Rac1 and Cdc42 Rho GTPases. J. Cell Sci. 120, 279– 288. 10.1242/jcs.03323 17200137 · DOI
  99. Mueller B. K. Mack H. Teusch N. (2005). Rho kinase, a promising drug target for neurological disorders. Nat. Rev. Drug Discov. 4, 387– 398. 10.1038/nrd1719 15864268 · DOI
  100. Musilli M. Ciotti M. T. Pieri M. Martino A. Borrelli S. Dinallo V.. (2016). Therapeutic effects of the Rho GTPase modulator CNF1 in a model of Parkinson’s disease. Neuropharmacology 109, 357– 365. 10.1016/j.neuropharm.2016.06.016 27350290 · DOI
  101. Musilli M. Nicolia V. Borrelli S. Scarpa S. Diana G. (2013). Behavioral effects of Rho GTPase modulation in a model of Alzheimer’s disease. Behav. Brain Res. 237, 223– 229. 10.1016/j.bbr.2012.09.043 23026376 · DOI
  102. Nakajima A. Ohizumi Y. (2019). Potential benefits of nobiletin, a citrus flavonoid, against Alzheimer’s disease and Parkinson’s disease. Int. J. Mol. Sci. 20: 3380. 10.3390/ijms20143380 31295812 PMC6678479 · DOI
  103. Narumiya S. (1996). The small GTPase Rho: cellular functions and signal transduction. J. Biochem. 120, 215– 228. 10.1093/oxfordjournals.jbchem.a021401 8889802 · DOI
  104. Nassar N. Cancelas J. Zheng J. Williams D. A. Zheng Y. (2006). Structure-function based design of small molecule inhibitors targeting Rho family GTPases. Curr. Top. Med. Chem. 6, 1109– 1116. 10.2174/156802606777812095 16842149 · DOI
  105. Oh D. Han S. Seo J. Lee J.-R. Choi J. Groffen J.. (2010). Regulation of synaptic Rac1 activity, long-term potentiation maintenance and learning and memory by BCR and ABR Rac GTPase-activating proteins. J. Neurosci. 30, 14134– 14144. 10.1523/JNEUROSCI.1711-10.2010 20962234 PMC5076888 · DOI
  106. Oprea T. I. Sklar L. A. Agola J. O. Guo Y. Silberberg M. Roxby J.. (2015). Novel activities of select NSAID R-Enantiomers against Rac1 and Cdc42 GTPases. PLoS One 10: e0142182. 10.1371/journal.pone.0142182 26558612 PMC4641600 · DOI
  107. Ozben T. Ozben S. (2019). Neuro-inflammation and anti-inflammatory treatment options for Alzheimer’s disease. Clin. Biochem. 72, 87– 89. 10.1016/j.clinbiochem.2019.04.001 30954437 · DOI · Paper page
  108. Paisán-Ruiz C. Lewis P. A. Singleton A. B. (2013). LRRK2: cause, risk and mechanism. J. Park. Dis. 3, 85– 103. 10.3233/JPD-130192 23938341 PMC3952583 · DOI
  109. Palsuledesai C. C. Surviladze Z. Waller A. Miscioscia T. F. Guo Y. Wu Y.. (2018). Activation of Rho Family GTPases by small molecules. ACS Chem. Biol. 13, 1514– 1524. 10.1021/acschembio.8b00038 29746086 PMC6006448 · DOI
  110. Park S. J. Park D. H. Kim D. H. Lee S. Yoon B. H. Jung W. Y.. (2010). The memory-enhancing effects of Euphoria longan fruit extract in mice. J. Ethnopharmacol. 128, 160– 165. 10.1016/j.jep.2010.01.001 20064595 · DOI
  111. Pelish H. E. Peterson J. R. Salvarezza S. B. Rodriguez-Boulan E. Chen J.-L. Stamnes M.. (2006). Secramine inhibits Cdc42-dependent functions in cells and Cdc42 activation in vitro. Nat. Chem. Biol. 2, 39– 46. 10.1038/nchembio751 16408091 · DOI
  112. Penzes P. Jones K. A.. (2008). Dendritic spine dynamics – a key role for kalirin-7. Trends Neurosci. 31, 419– 427. 10.1016/j.tins.2008.06.001 18597863 PMC3973420 · DOI · Paper page
  113. Petratos S. Li Q.-X. George A. J. Hou X. Kerr M. L. Unabia S. E.. (2008). The β-amyloid protein of Alzheimer’s disease increases neuronal CRMP-2 phosphorylation by a Rho-GTP mechanism. Brain 131, 90– 108. 10.1093/brain/awm260 18000012 · DOI · Paper page
  114. Pozueta J. Lefort R. Ribe E. M. Troy C. M. Arancio O. Shelanski M. (2013). Caspase-2 is required for dendritic spine and behavioural alterations in J20 APP transgenic mice. Nat. Commun. 4: 1939. 10.1038/ncomms2927 23748737 PMC4398315 · DOI
  115. Puigdellívol M. Cherubini M. Brito V. Giralt A. Suelves N. Ballesteros J.. (2015). A role for Kalirin-7 in corticostriatal synaptic dysfunction in Huntington’s disease. Hum. Mol. Genet. 24, 7265– 7285. 10.1093/hmg/ddv426 26464483 PMC4664166 · DOI
  116. Qu L. Pan C. He S.-M. Lang B. Gao G.-D. Wang X.-L.. (2019). The ras superfamily of small GTPases in Non-neoplastic cerebral diseases. Front. Mol. Neurosci. 12: 121. 10.3389/fnmol.2019.00121 31213978 PMC6555388 · DOI
  117. Ringholz G. M. Appel S. H. Bradshaw M. Cooke N. A. Mosnik D. M. Schulz P. E. (2005). Prevalence and patterns of cognitive impairment in sporadic ALS. Neurology 65, 586– 590. 10.1212/01.wnl.0000172911.39167.b6 16116120 · DOI
  118. Rosario M. Schuster S. Juttner R. Parthasarathy S. Tarabykin V. Birchmeier W. (2012). Neocortical dendritic complexity is controlled during development by NOMA-GAP-dependent inhibition of Cdc42 and activation of cofilin. Genes Dev. 26, 1743– 1757. 10.1101/gad.191593.112 22810622 PMC3418591 · DOI
  119. Safiulina D. Kuum M. Choubey V. Gogichaishvili N. Liiv J. Hickey M. A.. (2019). Miro proteins prime mitochondria for Parkin translocation and mitophagy. EMBO J. 38: e99384. 10.15252/embj.201899384 30504269 PMC6331716 · DOI
  120. Salloum G. Jaafar L. El-Sibai M. (2020). Rho A and Rac1: antagonists moving forward. Tissue Cell 65: 101364. 10.1016/j.tice.2020.101364 32746999 · DOI
  121. Scheiblich H. Bicker G. (2017). Regulation of microglial phagocytosis by RhoA/ROCK-Inhibiting drugs. Cell. Mol. Neurobiol. 37, 461– 473. 10.1007/s10571-016-0379-7 27178562 PMC11482106 · DOI · Paper page
  122. Sha J. Na J. Lee J. O. Kim N. Lee S. K. Kim J. H.. (2014). Vav3, a GEF for RhoA, plays a critical role under high glucose conditions. Endocrinol. Metab. 29, 363– 370. 10.3803/EnM.2014.29.3.363 25309796 PMC4192823 · DOI
  123. Shang X. Marchioni F. Sipes N. Evelyn C. R. Jerabek-Willemsen M. Duhr S.. (2012). Rational design of small molecule inhibitors targeting RhoA subfamily Rho GTPases. Chem. Biol. 19, 699– 710. 10.1016/j.chembiol.2012.05.009 22726684 PMC3383629 · DOI
  124. Shen W. Wu B. Zhang Z. Dou Y. Rao Z.-R. Chen Y.-R.. (2006). Activity-induced rapid synaptic maturation mediated by presynaptic cdc42 signaling. Neuron 50, 401– 414. 10.1016/j.neuron.2006.03.017 16675395 · DOI
  125. Singh I. Samuvel D. J. Choi S. Saxena N. Singh A. K. Won J. (2018). Combination therapy of lovastatin and AMP-activated protein kinase activator improves mitochondrial and peroxisomal functions and clinical disease in experimental autoimmune encephalomyelitis model. Immunology 154, 434– 451. 10.1111/imm.12893 29331024 PMC6002225 · DOI
  126. Sivadasan R. Hornburg D. Drepper C. Frank N. Jablonka S. Hansel A.. (2016). C9ORF72 interaction with cofilin modulates actin dynamics in motor neurons. Nat. Neurosci. 19, 1610– 1618. 10.1038/nn.4407 27723745 · DOI
  127. Socodato R. Portugal C. C. Canedo T. Rodrigues A. Almeida T. O. Henriques J. F.. (2020). Microglia dysfunction caused by the loss of rhoa disrupts neuronal physiology and leads to neurodegeneration. Cell Rep. 31: 107796. 10.1016/j.celrep.2020.107796 32579923 · DOI · Paper page
  128. Stankiewicz T. R. Linseman D. A. (2014). Rho family GTPases: key players in neuronal development, neuronal survival and neurodegeneration. Front. Cell. Neurosci. 8: 314. 10.3389/fncel.2014.00314 25339865 PMC4187614 · DOI · Paper page
  129. Stankiewicz T. R. Pena C. Bouchard R. J. Linseman D. A. (2020). Dysregulation of Rac or Rho elicits death of motor neurons and activation of these GTPases is altered in the G93A mutant hSOD1 mouse model of amyotrophic lateral sclerosis. Neurobiol. Dis. 136: 104743. 10.1016/j.nbd.2020.104743 31931138 PMC7020796 · DOI
  130. Steffen A. Stradal T. E. B. Rottner K. (2017). Signalling pathways controlling cellular actin organization. Handb. Exp. Pharmacol. 235, 153– 178. 10.1007/164_2016_35 27757765 · DOI
  131. Stephen T.-L. Higgs N. F. Sheehan D. F. Al Awabdh S. López-Doménech G. Arancibia-Carcamo I. L.. (2015). Miro1 regulates activity-driven positioning of mitochondria within astrocytic processes apposed to synapses to regulate intracellular calcium signaling. J. Neurosci. 35, 15996– 16011. 10.1523/JNEUROSCI.2068-15.2015 26631479 PMC4666922 · DOI
  132. Surviladze Z. Waller A. Strouse J. J. Bologa C. Ursu O. Salas V.. (2010). A Potent and Selective Inhibitor of Cdc42 GTPase, in Probe Reports From the NIH Molecular Libraries Program. Bethesda, MD: National Center for Biotechnology Information (US). Available online at: http://www.ncbi.nlm.nih.gov/books/NBK51965/. Accessed September 22, 2020. 21433396
  133. Takata M. Tanaka H. Kimura M. Nagahara Y. Tanaka K. Kawasaki K.. (2013). Fasudil, a rho kinase inhibitor, limits motor neuron loss in experimental models of amyotrophic lateral sclerosis. Br. J. Pharmacol. 170, 341– 351. 10.1111/bph.12277 23763343 PMC3834758 · DOI · Paper page
  134. Tan A. M. Samad O. A. Liu S. Bandaru S. Zhao P. Waxman S. G. (2013). Burn injury-induced mechanical allodynia is maintained by Rac1-regulated dendritic spine dysgenesis. Exp. Neurol. 248, 509– 519. 10.1016/j.expneurol.2013.07.017 23933578 · DOI
  135. Tantillo E. Colistra A. Vannini E. Cerri C. Pancrazi L. Baroncelli L.. (2018). Bacterial toxins and targeted brain therapy new insights from cytotoxic necrotizing factor 1 (CNF1). Int. J. Mol. Sci. 19: 1632. 10.3390/ijms19061632 29857515 PMC6032336 · DOI
  136. Tashiro A. Minden A. Yuste R. (2000). Regulation of dendritic spine morphology by the rho family of small GTPases: antagonistic roles of Rac and Rho. Cereb. Cortex 10, 927– 938. 10.1093/cercor/10.10.927 11007543 · DOI
  137. Tatenhorst L. Eckermann K. Dambeck V. Fonseca-Ornelas L. Walle H. Lopes da Fonseca T.. (2016). Fasudil attenuates aggregation of α-synuclein in models of Parkinson’s disease. Acta Neuropathol. Commun. 4: 39. 10.1186/s40478-016-0310-y 27101974 PMC4840958 · DOI · Paper page
  138. Tian C. Kay Y. Sadybekov A. Rao S. Katritch V. Herring B. E. (2018). An intellectual disability-related missense mutation in Rac1 prevents LTP induction. Front. Mol. Neurosci. 11: 223. 10.3389/fnmol.2018.00223 30042656 PMC6049044 · DOI
  139. Tiede I. Fritz G. Strand S. Poppe D. Dvorsky R. Strand D.. (2003). CD28-dependent Rac1 activation is the molecular target of azathioprine in primary human CD4+ T lymphocytes. J. Clin. Invest. 111, 1133– 1145. 10.1172/JCI16432 12697733 PMC152932 · DOI · Paper page
  140. Tolias K. F. Duman J. G. Um K. (2011). Control of synapse development and plasticity by Rho GTPase regulatory proteins. Prog. Neurobiol. 94, 133– 148. 10.1016/j.pneurobio.2011.04.011 21530608 PMC3129138 · DOI · Paper page
  141. Tönges L. Frank T. Tatenhorst L. Saal K. A. Koch J. C. Szego É. M.. (2012). Inhibition of rho kinase enhances survival of dopaminergic neurons and attenuates axonal loss in a mouse model of Parkinson’s disease. Brain 135, 3355– 3370. 10.1093/brain/aws254 23087045 PMC3501973 · DOI · Paper page
  142. Tourette C. Li B. Bell R. O’Hare S. Kaltenbach L. S. Mooney S. D.. (2014). A large scale Huntingtin protein interaction network implicates Rho GTPase signaling pathways in Huntington disease. J. Biol. Chem. 289, 6709– 6726. 10.1074/jbc.M113.523696 24407293 PMC3945331 · DOI
  143. Travaglione S. Loizzo S. Ballan G. Fiorentini C. Fabbri A. (2014). The E. coli CNF1 as a pioneering therapy for the central nervous system diseases. Toxins 6, 270– 282. 10.3390/toxins6010270 24402235 PMC3920261 · DOI
  144. Travaglione S. Loizzo S. Vona R. Ballan G. Rivabene R. Giordani D.. (2020). The bacterial toxin cnf1 protects human neuroblastoma sh-sy5y cells against 6-hydroxydopamine-induced cell damage: the hypothesis of cnf1-promoted autophagy as an antioxidant strategy. Int. J. Mol. Sci. 21: 3390. 10.3390/ijms21093390 32403292 PMC7247702 · DOI
  145. Tsai Y.-C. Riess O. Soehn A. S. Nguyen H. P. (2012). The guanine nucleotide exchange factor kalirin-7 is a novel synphilin-1 interacting protein and modifies synphilin-1 aggregate transport and formation. PLoS One 7: e51999. 10.1371/journal.pone.0051999 23284848 PMC3527391 · DOI
  146. Tseng Y.-T. Lin W.-J. Chang W.-H. Lo Y.-C. (2019). The novel protective effects of loganin against 1-methyl-4-phenylpyridinium-induced neurotoxicity: Enhancement of neurotrophic signaling, activation of IGF-1R/GLP-1R and inhibition of RhoA/ROCK pathway. Phytother. Res. PTR 33, 690– 701. 10.1002/ptr.6259 30556245 · DOI
  147. Turner T. N. Sharma K. Oh E. C. Liu Y. P. Collins R. L. Sosa M. X.. (2015). Loss of δ-catenin function in severe autism. Nature 520, 51– 56. 10.1038/nature14186 25807484 PMC4383723 · DOI
  148. Vadodaria K. C. Brakebusch C. Suter U. Jessberger S. (2013). Stage-specific functions of the small Rho GTPases Cdc42 and Rac1 for adult hippocampal neurogenesis. J. Neurosci. 33, 1179– 1189. 10.1523/JNEUROSCI.2103-12.2013 23325254 PMC6704849 · DOI
  149. Vaghi V. Pennucci R. Talpo F. Corbetta S. Montinaro V. Barone C.. (2014). Rac1 and rac3 GTPases control synergistically the development of cortical and hippocampal GABAergic interneurons. Cereb. Cortex 24, 1247– 1258. 10.1093/cercor/bhs402 23258346 PMC3977619 · DOI
  150. Valdez C. M. Murphy G. G. Beg A. A. (2016). The Rac-GAP alpha2-chimaerin regulates hippocampal dendrite and spine morphogenesis. Mol. Cell. Neurosci. 75, 14– 26. 10.1016/j.mcn.2016.06.002 27297944 PMC5023278 · DOI
  151. Wang P.-L. Niidome T. Akaike A. Kihara T. Sugimoto H. (2009). Rac1 inhibition negatively regulates transcriptional activity of the amyloid precursor protein gene. J. Neurosci. Res. 87, 2105– 2114. 10.1002/jnr.22039 19267423 · DOI
  152. Wang Q. Amato S. P. Rubitski D. M. Hayward M. M. Kormos B. L. Verhoest P. R.. (2016). Identification of phosphorylation consensus sequences and endogenous neuronal substrates of the psychiatric risk kinase tnik. J. Pharmacol. Exp. Ther. 356, 410– 423. 10.1124/jpet.115.229880 26645429 · DOI
  153. Xin Y.-L. Yu J.-Z. Yang X.-W. Liu C.-Y. Li Y.-H. Feng L.. (2015). FSD-C10: A more promising novel ROCK inhibitor than Fasudil for treatment of CNS autoimmunity. Biosci. Rep. 35: e00247. 10.1042/BSR20150032 26223433 PMC4721545 · DOI
  154. Yamaguchi H. Kasa M. Amano M. Kaibuchi K. Hakoshima T. (2006). Molecular mechanism for the regulation of rho-kinase by dimerization and its inhibition by fasudil. Structure 14, 589– 600. 10.1016/j.str.2005.11.024 16531242 · DOI
  155. Yamashita T. Tohyama M. (2003). The p75 receptor acts as a displacement factor that releases Rho from Rho-GDI. Nat. Neurosci. 6, 461– 467. 10.1038/nn1045 12692556 · DOI · Paper page
  156. Yan Y. Yu J. Gao Y. Kumar G. Guo M. Zhao Y.. (2019). Therapeutic potentials of the Rho kinase inhibitor Fasudil in experimental autoimmune encephalomyelitis and the related mechanisms. Metab. Brain Dis. 34, 377– 384. 10.1007/s11011-018-0355-7 30552558 · DOI
  157. Yang T. Knowles J. K. Lu Q. Zhang H. Arancio O. Moore L. A.. (2008). Small molecule, non-peptide p75 ligands inhibit Abeta-induced neurodegeneration and synaptic impairment. PLoS One 3: e3604. 10.1371/journal.pone.0003604 18978948 PMC2575383 · DOI
  158. Yang T. Tran K. C. Zeng A. Y. Massa S. M. Longo F. M. (2020). Small molecule modulation of the p75 neurotrophin receptor inhibits multiple amyloid beta-induced tau pathologies. Sci. Rep. 10: 20322. 10.1038/s41598-020-77210-y 33230162 PMC7683564 · DOI
  159. Youn H. Jeoung M. Koo Y. Ji H. Markesbery W. R. Ji I.. (2007). Kalirin is under-expressed in Alzheimer’s disease hippocampus. J. Alzheimers Dis. 11, 385– 397. 10.3233/jad-2007-11314 17851188 · DOI · Paper page
  160. Yu J.-Z. Li Y.-H. Liu C.-Y. Wang Q. Gu Q.-F. Wang H.-Q.. (2017). Multitarget therapeutic effect of fasudil in APP/PS1 transgenic mice. CNS Neurol. Disord. Drug Targets 16, 199– 209. 10.2174/1871527315666160711104719 27401064 · DOI
  161. Zamboni V. Jones R. Umbach A. Ammoni A. Passafaro M. Hirsch E.. (2018). Rho GTPases in intellectual disability: from genetics to therapeutic opportunities. Int. J. Mol. Sci. 19: 1821. 10.3390/ijms19061821 29925821 PMC6032284 · DOI · Paper page
  162. Zegers M. M. Friedl P. (2014). Rho GTPases in collective cell migration. Small GTPases 5: e28997. 10.4161/sgtp.28997 25054920 PMC4114924 · DOI
  163. Zhang Y.-T. Xu L.-H. Lu Q. Liu K.-P. Liu P.-Y. Ji F.. (2014). VASP activation via the Gα13/RhoA/PKA pathway mediates cucurbitacin-B-induced actin aggregation and cofilin-actin rod formation. PLoS One 9: e93547. 10.1371/journal.pone.0093547 24691407 PMC3972149 · DOI
  164. Zhao L. Ma Q.-L. Calon F. Harris-White M. E. Yang F. Lim G. P.. (2006). Role of p21-activated kinase pathway defects in the cognitive deficits of Alzheimer disease. Nat. Neurosci. 9, 234– 242. 10.1038/nn1630 16415866 · DOI · Paper page
  165. Zheleznyakova G. Y. Voisin S. Kiselev A. V. Sällman Almén M. Xavier M. J. Maretina M. A.. (2013). Genome-wide analysis shows association of epigenetic changes in regulators of Rab and Rho GTPases with spinal muscular atrophy severity. Eur. J. Hum. Genet. 21, 988– 993. 10.1038/ejhg.2012.293 23299920 PMC3746269 · DOI
  166. Zhou Y. Su Y. Li B. Liu F. Ryder J. W. Wu X.. (2003). Nonsteroidal anti-inflammatory drugs can lower amyloidogenic Aβ42 by inhibiting Rho. Science 302, 1215– 1217. 10.1126/science.1090154 14615541 · DOI · Paper page
  167. Zhu X. Raina A. K. Boux H. Simmons Z. L. Takeda A. Smith M. A. (2000). Activation of oncogenic pathways in degenerating neurons in Alzheimer disease. Int. J. Dev. Neurosci. 18, 433– 437. 10.1016/s0736-5748(00)00010-1 10817927 · DOI
  168. Zhu Y. Howard G. A. Pittman K. Boykin C. Herring L. E. Wilkerson E. M.. (2019). Therapeutic effect of Y-27632 on tumorigenesis and cisplatin-induced peripheral sensory loss through RhoA-NF-κB. Mol. Cancer Res. 17, 1910– 1919. 10.1158/1541-7786.MCR-19-0024 31189689 PMC6774348 · DOI
  169. Zins K. Gunawardhana S. Lucas T. Abraham D. Aharinejad S. (2013a). Targeting Cdc42 with the small molecule drug AZA197 suppresses primary colon cancer growth and prolongs survival in a preclinical mouse xenograft model by downregulation of PAK1 activity. J. Transl. Med. 11: 295. 10.1186/1479-5876-11-295 24279335 PMC4222769 · DOI
  170. Zins K. Lucas T. Reichl P. Abraham D. Aharinejad S. (2013b). A Rac1/Cdc42 GTPase-specific small molecule inhibitor suppresses growth of primary human prostate cancer xenografts and prolongs survival in mice. PLoS One 8: e74924. 10.1371/journal.pone.0074924 24040362 PMC3770583 · DOI

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Authors
Guiler, W., Koehler, A., Boykin, C., & Lu, Q.
Affiliations
East Carolina University (US)
Corresponding author
Lu, Qun
ORCID
Venue
Frontiers in Cellular Neuroscience
Publisher
Frontiers Media SA
Published
2021-05-12
Volume
15
Pages
661612-661612
ISSN
1662-5102 (ISSN-L)
DOI
10.3389/fncel.2021.661612
PMC
PMC8149604
OpenAlex
W3160713297
Cited by
51
References
5
Citations by year
2026: 7 · 2025: 7 · 2024: 10 · 2023: 9 · 2022: 16 · 2021: 2
FWCI
2.90
Type
journal article
Language
en
Open access
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  • Frontiers in Cellular Neuroscience (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
Funders
  • National Institutes of Health
  • National Cancer Institute (R15CA165202)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Kinase Regulation and GTPase Signaling
  • Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
  • Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
Keywords
Rho GTPases, RhoA, Rac1, Cdc42, small molecule modulators, GEF, GaP, neurodegenerative diseases, Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, frontotemporal dementia, multiple sclerosis, nonsteroidal anti-inflammatory drugs, natural products, toxins, therapeutic target

About these checks

Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.

Statistics and arithmetic are recomputed, not judged.

Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.

What counts as a claim ›How we measure confidence ›How we check this ›

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