Valina L. Dawson
Valina L. Dawson (born August 5, 1961) is an American neuroscientist who is the director of the Programs in Neuroregeneration and Stem Cells at the Institute for Cell Engineering at the Johns Hopkins University School of Medicine. She has joint appointments in the Department of Neurology,[1] Neuroscience [2] and Physiology.[3] She is a member of the Graduate Program in Cellular and Molecular Medicine and Biochemistry, Cellular and Molecular Biology.
Biography
Dawson grew up in the Sonoma Valley Wine Country in California. Dawson received her B.S. in environmental toxicology in 1983 from the University of California, Davis. She earned her Ph.D. in pharmacology and toxicology from the University of Utah School of Medicine. Postdoctoral training was conducted at the University of Pennsylvania and the National Institute on Drug Abuse Addiction Research Center. Dawson joined the faculty at Johns Hopkins University School of Medicine in 1994 as an assistant professor in the departments of Neurology, Neuroscience and Physiology. In 2001, she became an associate professor in the departments of Neurology, Neuroscience and Physiology and served as the vice chair of faculty development in the department of Neurology. Dawson was promoted to the position of professor in the departments of Neurology, Neuroscience and Physiology in 2001. In 2002, she founded the Neuroregeneration Program in the Institute of Cell Engineering[4] and became director of the Stem Cell Program in 2009. She was named a Daniel Nathans Innovator in 2017. She served the Society for Neuroscience as a reviewing editor (2003–2009) and then as a senior editor (2010–2016) for the Journal of Neuroscience and is now serving as an advisory board editor for the other society journal, eNeuro. She also served the Society for Neuroscience on the Committee on Women in Neuroscience (2007–2010), professional development committee (2009–2011) and the program committee (2011–2014). She serves on the scientific advisory board of the New York Stem Cell Foundation, the Weill Cornell Burke Medical Research Institute [5] the external advisory board for the Interdepartmental Neuroscience (NUIN) graduate training program at Northwestern University, and the advisory board for NeuroMab.[6] She was a founder of AGY Therapeutics.[7] She is a founder and is on the scientific advisory board of Neuraly and Valted, LLC.
Research
Dawson works closely with her husband and partner, Dr. Ted M. Dawson. Their research studies the molecular mechanisms that lead to neuronal cell death in neurodegenerative diseases, stroke and trauma. They discovered the critical role the gasous transmitter, nitric oxide (NO), plays in glutamate excitotoxicity[8][9] and stroke[10] with their postdoctoral mentor, Dr. Solomon H. Snyder. They defined the role for NO generated from neuronal NO synthase or immunologic NO synthase leads in models of HIV dementia[11][12] and Parkinson’s disease.[13][14] Exploring the signaling cascade led to the identification of peroxynitrite as the nitrogen oxide moiety that mediates neurotoxicity, and the role for poly(ADP-ribose) polymerase (PARP) [15][16] as the next step in the neurotoxic cascade. They discovered that poly (ADP-ribose) polymer (PAR) is a novel cell death signaling molecule that plays a critical role in neuronal injury.[17][18] Her research team discovered that PAR leads to cell death by facilitating the release of apoptosis inducing factor (AIF) factor[19][20] from the mitochondrial surface.[21] Parsylated AIF then recruits macrophage migration inhibitory factor (MIF) and the complex translocates to the nucleus where the nuclease activity of MIF leads to large scale DNA fragmentation.[22] To distinguish this form of cell death from other cell death signaling cascades[23] it was named Parthanatos, for PAR and the Greek god of death, Thanatos.[24] The enzyme that degrades PAR, poly (ADP-ribose) glycohydrolase, is not only an endogenous negative regulator of parthanatos, but required for cell viability.[25] In genetic screens to find cell signals that prevent neurotoxicity, her team discovered an endogenous inhibitor of parthanatos, Iduna (RNF146), a first in class PAR-dependent E3 ligase.[26][27] In the same screens, Botch was discovered which is an important inhibitor of Notch signaling via deglycination of Notch preventing Notch’s intracellular processing at the level of the Golgi, playing an important role in neuronal development and survival.[28][29] They also discovered Thorase, an AAA+ ATPase that regulates glutamate (AMPA) receptor trafficking and discovered that Thorase is an important regulator of synaptic plasticity, learning and memory.[30] Genetic variants of Thorase were found in schizophrenic patients. Expression of these variants in mice lead to behavioral deficits that were normalized with the AMPA antagonist Parampenal.[31] Mutations in Thorase leading to gain or loss of function result in lethal developmental disorders in children.[32][33]
With the discovery of gene mutations that are the cause of rare familial cases of Parkinson’s disease, their research team has probed the biologic and pathologic actions of these proteins. They discovered parkin was an E3 ligase that is inactive in patients with genetic mutations in parkin,[34] and that it is also inactive in sporadic Parkinson’s disease due to protein modifications by S-nitrosylation[35] and c-Abl tyrosine phosphorylation[36] which led to the discovery of the pathogenic targets, PARIS and AIMP2.[37] PARIS regulates the machinery critical to mitochondrial quality control and thus cell survival.[38] Surprisingly, AIMP2 directly interacts with PARP and activates Parthanatos.[39] Since there are PARP inhibitors in clinical use this finding may provide a new therapeutic target for the treatment of Parkinson’s disease. They discovered that DJ-1, which is dysfunctional in Parkinson’s disease, is an atypical peroxidoxin-like peroxidase and that its loss of function in PD leads to mitochondrial dysfunction.[40] The Dawson’s discovered that mutations in LRRK2 increase its kinase activity[41][42] and that inhibition of LRRK2 kinase activity is protective in models of Parkinson’s disease.[43] The increase in LRRK2 kinase activity leads to enhanced protein translation via the phosphorylation of the ribosomal protein s15.[44] Understanding this shift in the proteome due to altered translation will allow new insight into the alteration in expression of critical proteins that likely underlie the pathogenesis of Parkinson’s disease. ArfGAP regulates the GTPase activity of LRRK2 and they discovered that ArfGAP and LRRK2 reciprocally regulate the activity of each other determining neuronal viability.[45] Their labs also discovered that pathologic α-synuclein spreads in the nervous system via engagement with the lymphocyte-activation gene 3 (LAG3).[46] They discovered that Glucagon-like peptide-1 receptor (GLP1R) agonist, NLY01 prevents neuroinflammaory damage induced by pathologic α-synuclein in Parkinson’s disease via inhibition of microglia and prevention of the conversion of resting astrocytes to activated A1 astrocytes.[47] Their work continues to provide critical insights into understanding of the pathogenesis of PD and identify new opportunities for therapies to treat patients with Parkinson’s disease. Valina Dawson has published over 400 publications and has an H-index of 129.[48]
Awards
- Debrecen Award for Molecular Medicine (2019)[49]
- Distinguished professorship, Xiangya Hospital, Central South University, Changsha, China[50]
- Danial Nathans Innovator Award
- Thomson Reuters Highly Cited Researcher and Worlds Most Influential Minds,
- Elected Fellow of the American Heart Association (F.A.H.A.)
- Elected Fellow of the American Association for the Advancement of Science
- Elected to the American Neurological Association, Fellow
- Javits Neuroscience Investigator Award
- Potter Lectureship, Thomas Jefferson University
- Frontiers in Clinical Neuroscience American Academy of Neurology
References
- "Neurology and Neurosurgery". Hopkinsmedicine.org. Retrieved 23 October 2018.
- "The Solomon H Snyder Department of Neuroscience". Neuroscience.jhu.edu. Retrieved 23 October 2018.
- "Department of Physiology". Department of Physiology. Retrieved 23 October 2018.
- "The Johns Hopkins Institute for Cell Engineering (ICE) in Baltimore, Maryland". Hopkinsmedicine.org. Retrieved 23 October 2018.
- "Our Role & Cause". Burke.weill.cornell.edu. Retrieved 23 October 2018.
- "Welcome to NeuroMab!". Neuromab.ucdavis.edu. Retrieved 23 October 2018.
- "AGY Therapeutics Inc". Agyinc.com. Retrieved 23 October 2018.
- Dawson, V.L.; et al. (1991). "Nitric oxide mediates glutamate neurotoxicity in primary cortical cultures". Proc Natl Acad Sci U S A. 88 (14): 6368–6371. Bibcode:1991PNAS...88.6368D. doi:10.1073/pnas.88.14.6368. PMC 52084. PMID 1648740.
- Dawson, V.L.; et al. (1993). "Mechanisms of nitric oxide-mediated neurotoxicity in primary brain cultures". J. Neurosci. 13 (6): 2651–61. doi:10.1523/jneurosci.13-06-02651.1993. PMID 7684776.
- Dawson, V.L.; et al. (1996). "Resistance to neurotoxicity in cortical cultures from neuronal nitric oxide synthase-deficient mice". J. Neurosci. 16 (8): 2479–87. doi:10.1523/jneurosci.16-08-02479.1996. PMID 8786424.
- Dawson, V.L.; et al. (1993). "Human immunodeficiency virus type 1 coat protein neurotoxicity mediated by nitric oxide in primary cortical cultures". Proc Natl Acad Sci U S A. 90 (8): 3256–3259. Bibcode:1993PNAS...90.3256D. doi:10.1073/pnas.90.8.3256. PMC 46278. PMID 8097316.
- Adamson, D.C.; et al. (1996). "Immunologic NO synthase: elevation in severe AIDS dementia and induction by HIV-1 gp41". Science. 274 (5294): 1917–21. Bibcode:1996Sci...274.1917C. doi:10.1126/science.274.5294.1917. PMID 8943206.
- Przedborski, S.; et al. (1996). "Role of neuronal nitric oxide in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced dopaminergic neurotoxicity". Proc Natl Acad Sci U S A. 93 (10): 4565–4571. Bibcode:1996PNAS...93.4565P. doi:10.1073/pnas.93.10.4565. PMC 39317. PMID 8643444.
- Liberatore, GT; Jackson-Lewis, V; Vukosavic, S; Mandir, AS; Vila, M; McAuliffe, WG; Dawson, VL; Dawson, TM; Przedborski, S (December 1999). "Inducible nitric oxide synthase stimulates dopaminergic neurodegeneration in the MPTP model of Parkinson disease". Nature Medicine. 5 (12): 1403–9. doi:10.1038/70978. PMID 10581083.
- Zhang, J; Dawson, VL; Dawson, TM; Snyder, SH (4 February 1994). "Nitric oxide activation of poly(ADP-ribose) synthetase in neurotoxicity". Science. 263 (5147): 687–9. Bibcode:1994Sci...263..687Z. doi:10.1126/science.8080500. PMID 8080500.
- Eliasson, MJ; Sampei, K; Mandir, AS; Hurn, PD; Traystman, RJ; Bao, J; Pieper, A; Wang, ZQ; Dawson, TM; Snyder, SH; Dawson, VL (October 1997). "Poly(ADP-ribose) polymerase gene disruption renders mice resistant to cerebral ischemia". Nature Medicine. 3 (10): 1089–95. doi:10.1038/nm1097-1089. PMID 9334719.
- Yu, SW; Andrabi, SA; Wang, H; Kim, NS; Poirier, GG; Dawson, TM; Dawson, VL (28 November 2006). "Apoptosis-inducing factor mediates poly(ADP-ribose) (PAR) polymer-induced cell death". Proceedings of the National Academy of Sciences of the United States of America. 103 (48): 18314–9. Bibcode:2006PNAS..10318314Y. doi:10.1073/pnas.0606528103. PMC 1838748. PMID 17116881.
- Andrabi, SA; Kim, NS; Yu, SW; Wang, H; Koh, DW; Sasaki, M; Klaus, JA; Otsuka, T; Zhang, Z; Koehler, RC; Hurn, PD; Poirier, GG; Dawson, VL; Dawson, TM (28 November 2006). "Poly(ADP-ribose) (PAR) polymer is a death signal". Proceedings of the National Academy of Sciences of the United States of America. 103 (48): 18308–13. Bibcode:2006PNAS..10318308A. doi:10.1073/pnas.0606526103. PMC 1838747. PMID 17116882.
- Yu, SW; Wang, H; Poitras, MF; Coombs, C; Bowers, WJ; Federoff, HJ; Poirier, GG; Dawson, TM; Dawson, VL (12 July 2002). "Mediation of poly(ADP-ribose) polymerase-1-dependent cell death by apoptosis-inducing factor". Science. 297 (5579): 259–63. Bibcode:2002Sci...297..259Y. doi:10.1126/science.1072221. PMID 12114629.
- Wang, Y; Kim, NS; Haince, JF; Kang, HC; David, KK; Andrabi, SA; Poirier, GG; Dawson, VL; Dawson, TM (5 April 2011). "Poly(ADP-ribose) (PAR) binding to apoptosis-inducing factor is critical for PAR polymerase-1-dependent cell death (parthanatos)". Science Signaling. 4 (167): ra20. doi:10.1126/scisignal.2000902. PMC 3086524. PMID 21467298.
- Yu, SW; Wang, Y; Frydenlund, DS; Ottersen, OP; Dawson, VL; Dawson, TM (18 November 2009). "Outer mitochondrial membrane localization of apoptosis-inducing factor: mechanistic implications for release". ASN Neuro. 1 (5): AN20090046. doi:10.1042/AN20090046. PMC 2784601. PMID 19863494.
- Wang, Y; An, R; Umanah, GK; Park, H; Nambiar, K; Eacker, SM; Kim, B; Bao, L; Harraz, MM; Chang, C; Chen, R; Wang, JE; Kam, TI; Jeong, JS; Xie, Z; Neifert, S; Qian, J; Andrabi, SA; Blackshaw, S; Zhu, H; Song, H; Ming, GL; Dawson, VL; Dawson, TM (7 October 2016). "A nuclease that mediates cell death induced by DNA damage and poly(ADP-ribose) polymerase-1". Science. 354 (6308): aad6872. doi:10.1126/science.aad6872. PMC 5134926. PMID 27846469.
- Galluzzi, L; et al. (March 2018). "Molecular mechanisms of cell death: recommendations of the Nomenclature Committee on Cell Death 2018". Cell Death and Differentiation. 25 (3): 486–541. doi:10.1038/s41418-017-0012-4. hdl:1721.1/116948. PMC 5864239. PMID 29362479.
- David, KK; Andrabi, SA; Dawson, TM; Dawson, VL (1 January 2009). "Parthanatos, a messenger of death". Frontiers in Bioscience (Landmark Edition). 14 (14): 1116–28. doi:10.2741/3297. PMC 4450718. PMID 19273119.
- Koh, DW; Lawler, AM; Poitras, MF; Sasaki, M; Wattler, S; Nehls, MC; Stöger, T; Poirier, GG; Dawson, VL; Dawson, TM (21 December 2004). "Failure to degrade poly(ADP-ribose) causes increased sensitivity to cytotoxicity and early embryonic lethality". Proceedings of the National Academy of Sciences of the United States of America. 101 (51): 17699–704. Bibcode:2004PNAS..10117699K. doi:10.1073/pnas.0406182101. PMC 539714. PMID 15591342.
- Andrabi, SA; Kang, HC; Haince, JF; Lee, YI; Zhang, J; Chi, Z; West, AB; Koehler, RC; Poirier, GG; Dawson, TM; Dawson, VL (June 2011). "Iduna protects the brain from glutamate excitotoxicity and stroke by interfering with poly(ADP-ribose) polymer-induced cell death". Nature Medicine. 17 (6): 692–9. doi:10.1038/nm.2387. PMC 3709257. PMID 21602803.
- Kang, HC; Lee, YI; Shin, JH; Andrabi, SA; Chi, Z; Gagné, JP; Lee, Y; Ko, HS; Lee, BD; Poirier, GG; Dawson, VL; Dawson, TM (23 August 2011). "Iduna is a poly(ADP-ribose) (PAR)-dependent E3 ubiquitin ligase that regulates DNA damage". Proceedings of the National Academy of Sciences of the United States of America. 108 (34): 14103–8. Bibcode:2011PNAS..10814103K. doi:10.1073/pnas.1108799108. PMC 3161609. PMID 21825151.
- Chi, Z; Zhang, J; Tokunaga, A; Harraz, MM; Byrne, ST; Dolinko, A; Xu, J; Blackshaw, S; Gaiano, N; Dawson, TM; Dawson, VL (17 April 2012). "Botch promotes neurogenesis by antagonizing Notch". Developmental Cell. 22 (4): 707–20. doi:10.1016/j.devcel.2012.02.011. PMC 3331935. PMID 22445366.
- Chi, Z; Byrne, ST; Dolinko, A; Harraz, MM; Kim, MS; Umanah, G; Zhong, J; Chen, R; Zhang, J; Xu, J; Chen, L; Pandey, A; Dawson, TM; Dawson, VL (8 May 2014). "Botch is a γ-glutamyl cyclotransferase that deglycinates and antagonizes Notch". Cell Reports. 7 (3): 681–8. doi:10.1016/j.celrep.2014.03.048. PMC 4031649. PMID 24767995.
- Zhang, J; Wang, Y; Chi, Z; Keuss, MJ; Pai, YM; Kang, HC; Shin, JH; Bugayenko, A; Wang, H; Xiong, Y; Pletnikov, MV; Mattson, MP; Dawson, TM; Dawson, VL (15 April 2011). "The AAA+ ATPase Thorase regulates AMPA receptor-dependent synaptic plasticity and behavior". Cell. 145 (2): 284–99. doi:10.1016/j.cell.2011.03.016. PMC 3085003. PMID 21496646.
- Umanah, GKE; et al. (13 December 2017). "Thorase variants are associated with defects in glutamatergic neurotransmission that can be rescued by Perampanel". Science Translational Medicine. 9 (420): eaah4985. doi:10.1126/scitranslmed.aah4985. PMC 6573025. PMID 29237760.
- Ahrens-Nicklas, RC; Umanah, GK; Sondheimer, N; Deardorff, MA; Wilkens, AB; Conlin, LK; Santani, AB; Nesbitt, A; Juulsola, J; Ma, E; Dawson, TM; Dawson, VL; Marsh, ED (February 2017). "Precision therapy for a new disorder of AMPA receptor recycling due to mutations in ATAD1". Neurology. Genetics. 3 (1): e130. doi:10.1212/NXG.0000000000000130. PMC 5289017. PMID 28180185.
- Piard, J; et al. (30 January 2018). "A homozygous ATAD1 mutation impairs postsynaptic AMPA receptor trafficking and causes a lethal encephalopathy". Brain : A Journal of Neurology. 141 (3): 651–661. doi:10.1093/brain/awx377. PMC 5837721. PMID 29390050.
- Zhang, Y; Gao, J; Chung, KK; Huang, H; Dawson, VL; Dawson, TM (21 November 2000). "Parkin functions as an E2-dependent ubiquitin- protein ligase and promotes the degradation of the synaptic vesicle-associated protein, CDCrel-1". Proceedings of the National Academy of Sciences of the United States of America. 97 (24): 13354–9. Bibcode:2000PNAS...9713354Z. doi:10.1073/pnas.240347797. PMC 27228. PMID 11078524.
- Chung, KK; Thomas, B; Li, X; Pletnikova, O; Troncoso, JC; Marsh, L; Dawson, VL; Dawson, TM (28 May 2004). "S-nitrosylation of parkin regulates ubiquitination and compromises parkin's protective function". Science. 304 (5675): 1328–31. Bibcode:2004Sci...304.1328C. doi:10.1126/science.1093891. PMID 15105460.
- Ko, HS; Lee, Y; Shin, JH; Karuppagounder, SS; Gadad, BS; Koleske, AJ; Pletnikova, O; Troncoso, JC; Dawson, VL; Dawson, TM (21 September 2010). "Phosphorylation by the c-Abl protein tyrosine kinase inhibits parkin's ubiquitination and protective function". Proceedings of the National Academy of Sciences of the United States of America. 107 (38): 16691–6. Bibcode:2010PNAS..10716691K. doi:10.1073/pnas.1006083107. PMC 2944759. PMID 20823226.
- Ko, HS; von Coelln, R; Sriram, SR; Kim, SW; Chung, KK; Pletnikova, O; Troncoso, J; Johnson, B; Saffary, R; Goh, EL; Song, H; Park, BJ; Kim, MJ; Kim, S; Dawson, VL; Dawson, TM (31 August 2005). "Accumulation of the authentic parkin substrate aminoacyl-tRNA synthetase cofactor, p38/JTV-1, leads to catecholaminergic cell death". The Journal of Neuroscience. 25 (35): 7968–78. doi:10.1523/JNEUROSCI.2172-05.2005. PMC 6725452. PMID 16135753.
- Shin, JH; Ko, HS; Kang, H; Lee, Y; Lee, YI; Pletinkova, O; Troconso, JC; Dawson, VL; Dawson, TM (4 March 2011). "PARIS (ZNF746) repression of PGC-1α contributes to neurodegeneration in Parkinson's disease". Cell. 144 (5): 689–702. doi:10.1016/j.cell.2011.02.010. PMC 3063894. PMID 21376232.
- Lee, Y; Karuppagounder, SS; Shin, JH; Lee, YI; Ko, HS; Swing, D; Jiang, H; Kang, SU; Lee, BD; Kang, HC; Kim, D; Tessarollo, L; Dawson, VL; Dawson, TM (October 2013). "Parthanatos mediates AIMP2-activated age-dependent dopaminergic neuronal loss". Nature Neuroscience. 16 (10): 1392–400. doi:10.1038/nn.3500. PMC 3785563. PMID 23974709.
- Andres-Mateos, E; Perier, C; Zhang, L; Blanchard-Fillion, B; Greco, TM; Thomas, B; Ko, HS; Sasaki, M; Ischiropoulos, H; Przedborski, S; Dawson, TM; Dawson, VL (11 September 2007). "DJ-1 gene deletion reveals that DJ-1 is an atypical peroxiredoxin-like peroxidase". Proceedings of the National Academy of Sciences of the United States of America. 104 (37): 14807–12. Bibcode:2007PNAS..10414807A. doi:10.1073/pnas.0703219104. PMC 1976193. PMID 17766438.
- West, AB; Moore, DJ; Biskup, S; Bugayenko, A; Smith, WW; Ross, CA; Dawson, VL; Dawson, TM (15 November 2005). "Parkinson's disease-associated mutations in leucine-rich repeat kinase 2 augment kinase activity". Proceedings of the National Academy of Sciences of the United States of America. 102 (46): 16842–7. doi:10.1073/pnas.0507360102. PMC 1283829. PMID 16269541.
- Smith, WW; Pei, Z; Jiang, H; Moore, DJ; Liang, Y; West, AB; Dawson, VL; Dawson, TM; Ross, CA (20 December 2005). "Leucine-rich repeat kinase 2 (LRRK2) interacts with parkin, and mutant LRRK2 induces neuronal degeneration". Proceedings of the National Academy of Sciences of the United States of America. 102 (51): 18676–81. Bibcode:2005PNAS..10218676S. doi:10.1073/pnas.0508052102. PMC 1317945. PMID 16352719.
- Lee, BD; Shin, JH; VanKampen, J; Petrucelli, L; West, AB; Ko, HS; Lee, YI; Maguire-Zeiss, KA; Bowers, WJ; Federoff, HJ; Dawson, VL; Dawson, TM (September 2010). "Inhibitors of leucine-rich repeat kinase-2 protect against models of Parkinson's disease". Nature Medicine. 16 (9): 998–1000. doi:10.1038/nm.2199. PMC 2935926. PMID 20729864.
- Martin, I; et al. (10 April 2014). "Ribosomal protein s15 phosphorylation mediates LRRK2 neurodegeneration in Parkinson's disease". Cell. 157 (2): 472–485. doi:10.1016/j.cell.2014.01.064. PMC 4040530. PMID 24725412.
- Xiong, Y; Yuan, C; Chen, R; Dawson, TM; Dawson, VL (14 March 2012). "ArfGAP1 is a GTPase activating protein for LRRK2: reciprocal regulation of ArfGAP1 by LRRK2". The Journal of Neuroscience. 32 (11): 3877–86. doi:10.1523/JNEUROSCI.4566-11.2012. PMC 3319331. PMID 22423108.
- Mao, X; et al. (30 September 2016). "Pathological α-synuclein transmission initiated by binding lymphocyte-activation gene 3". Science. 353 (6307): aah3374. doi:10.1126/science.aah3374. PMC 5510615. PMID 27708076.
- Yun, S.P.; et al. (2018). "Block of A1 astrocyte conversion by microglia is neuroprotective in models of Parkinson's disease". Nat Med. 24 (7): 931–938. doi:10.1038/s41591-018-0051-5. PMC 6039259. PMID 29892066.
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