RECENT TOPICS

PAANIB-1: a Potential Treatment for Parkinson's Disease

Animation created by Sarrah Hussain, MA through collaboration with Drs. Ted and Valina Dawson. Thesis project completed in fulfillment of the Master of Arts in Medical & Biological Illustration degree at Johns Hopkins University School of Medicine. Any material contained in this video may not be manipulated, extracted, reproduced, or distributed without permission. © 2024 Sarrah Hussain

Gut-brain Connection in Parkinson's Disease

Animation created by Susie Yun, MA through collaboration with Drs. Ted and Valina Dawson. Thesis project completed in fulfillment of the Master of Arts in Medical & Biological Illustration degree at Johns Hopkins University School of Medicine. Any material contained in this video may not be manipulated, extracted, reproduced, or distributed without permission. © 2021 Susie Yun

PUBLICATIONS

α-Synuclein and mTORC1 in Parkinson's Models

  • Khan MR, Yin X, Kang SU, Mitra J, Wang H, Ryu T, Brahmachari S, Karuppagounder SS, Kimura Y, Jhaldiyal A, Kim HH, Gu H, Chen R, Redding-Ochoa J, Troncoso J, Na CH, Ha T, Dawson VL*, Dawson TM*. Enhanced mTORC1 signaling and protein synthesis in pathologic α-synuclein cellular and animal models of Parkinson's disease. Sci Transl Med. 2023 Nov 29;15(724):eadd0499. doi: 10.1126/scitranslmed.add0499. Epub 2023 Nov 29. PMID: 38019930.

Innate Immune Responses in Parkinson's Pathogenesis 

  • Panicker N, Kam TI, Wang H, Neifert S, Chou SC, Kumar M, Brahmachari S, Jhaldiyal A, Hinkle JT, Akkentli F, Mao X, Xu E, Karuppagounder SS, Hsu ET, Kang SU, Pletnikova O, Troncoso J, Dawson VL*, Dawson TM*. Neuronal NLRP3 is a parkin substrate that drives neurodegeneration in Parkinson's disease. Neuron. 2022 Aug 3;110(15):2422-2437.e9. doi: 10.1016/j.neuron.2022.05.009. Epub 2022 Jun 1. PMID: 35654037; PMCID: PMC9357148. 

  • Hinkle JT, Patel J, Panicker N, Karuppagounder SS, Biswas D, Belingon B, Chen R, Brahmachari S, Pletnikova O, Troncoso JC, Dawson VL*, Dawson TM*. STING mediates neurodegeneration and neuroinflammation in nigrostriatal α-synucleinopathy. Proc Natl Acad Sci U S A. 2022 Apr 12;119(15):e2118819119. doi: 10.1073/pnas.2118819119. Epub 2022 Apr 8. PMID: 35394877; PMCID: PMC9169780. 

Gut-Brain Axis in Parkinson's Disease 

  • Kim S, Kwon SH, Kam TI, Panicker N, Karuppagounder SS, Lee S, Lee JH, Kim WR, Kook M, Foss CA, Shen C, Lee H, Kulkarni S, Pasricha PJ, Lee G, Pomper MG, Dawson VL*, Dawson TM*, Ko HS. Transneuronal Propagation of Pathologic α-Synuclein from the Gut to the Brain Models Parkinson's Disease. Neuron. 2019 Aug 21;103(4):627-641.e7. doi: 10.1016/j.neuron.2019.05.035. Epub 2019 Jun 26. PMID: 31255487; PMCID: PMC6706297. 

Nitric Oxide in Parkinson's Neurotoxicity 

  • Dawson VL*, Dawson TM*, London ED, Bredt DS, Snyder SH. Nitric oxide mediates glutamate neurotoxicity in primary cortical cultures. Proc Natl Acad Sci U S A. 1991 Jul 15;88(14):6368-71. doi: 10.1073/pnas.88.14.6368. PMID: 1648740; PMCID: PMC52084. 

  • Dawson TM*, Bredt DS, Fotuhi M, Hwang PM, Snyder SH. Nitric oxide synthase and neuronal NADPH diaphorase are identical in brain and peripheral tissues. Proc Natl Acad Sci U S A. 1991 Sep 1;88(17):7797-801. doi: 10.1073/pnas.88.17.7797. PMID: 1715581; PMCID: PMC52390.

  • Adamson DC, Wildemann B, Sasaki M, Glass JD, McArthur JC, Christov VI, Dawson TM*, Dawson VL*. Immunologic NO synthase: elevation in severe AIDS dementia and induction by HIV-1 gp41. Science. 1996 Dec 13;274(5294):1917-21. doi: 10.1126/science.274.5294.1917. PMID: 8943206. 

  • Przedborski S, Jackson-Lewis V, Yokoyama R, Shibata T, Dawson VL*, Dawson TM*. 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. 1996 May 14;93(10):4565-71. doi: 10.1073/pnas.93.10.4565. PMID: 8643444; PMCID: PMC39317. 

  • Liberatore GT, Jackson-Lewis V, Vukosavic S, Mandir AS, Vila M, McAuliffe WG, Dawson VL*, Dawson TM*, Przedborski S. Inducible nitric oxide synthase stimulates dopaminergic neurodegeneration in the MPTP model of Parkinson disease. Nat Med. 1999 Dec;5(12):1403-9. doi: 10.1038/70978. PMID: 10581083. 

PARP Activation in NO-Induced Neurodegeneration 

  • Zhang J, Dawson VL*, Dawson TM*, Snyder SH. Nitric oxide activation of poly(ADP-ribose) synthetase in neurotoxicity. Science. 1994 Feb 4;263(5147):687-9. 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*. Poly(ADP-ribose) polymerase gene disruption renders mice resistant to cerebral ischemia. Nat Med. 1997 Oct;3(10):1089-95. doi: 10.1038/nm1097-1089. PMID: 9334719. 

  • Mandir AS, Przedborski S, Jackson-Lewis V, Wang ZQ, Simbulan-Rosenthal CM, Smulson ME, Hoffman BE, Guastella DB, Dawson VL*, Dawson TM*. Poly(ADP-ribose) polymerase activation mediates 1-methyl-4-phenyl-1, 2,3,6-tetrahydropyridine (MPTP)-induced parkinsonism. Proc Natl Acad Sci U S A. 1999 May 11;96(10):5774-9. doi: 10.1073/pnas.96.10.5774. PMID: 10318960; PMCID: PMC21936.  

  • Xu JC, Fan J, Wang X, Eacker SM, Kam TI, Chen L, Yin X, Zhu J, Chi Z, Jiang H, Chen R, Dawson TM*, Dawson VL*. Cultured networks of excitatory projection neurons and inhibitory interneurons for studying human cortical neurotoxicity. Sci Transl Med. 2016 Apr 6;8(333):333ra48. doi: 10.1126/scitranslmed.aad0623. PMID: 27053772; PMCID: PMC5595216. 

AIF-Mediated Cell Death in PARP Activation 

  • Yu SW, Wang H, Poitras MF, Coombs C, Bowers WJ, Federoff HJ, Poirier GG, Dawson TM*, Dawson VL*. Mediation of poly(ADP-ribose) polymerase-1-dependent cell death by apoptosis-inducing factor. Science. 2002 Jul 12;297(5579):259-63. doi: 10.1126/science.1072221. PMID: 12114629. 

PARKIN-Mediated Ubiquitination in Parkinson's Disease 

  • Zhang Y, Gao J, Chung KK, Huang H, Dawson VL*, Dawson TM*. Parkin functions as an E2-dependent ubiquitin- protein ligase and promotes the degradation of the synaptic vesicle-associated protein, CDCrel-1. Proc Natl Acad Sci U S A. 2000 Nov 21;97(24):13354-9. doi: 10.1073/pnas.240347797. PMID: 11078524; PMCID: PMC27228. 

  • Chung KK, Zhang Y, Lim KL, Tanaka Y, Huang H, Gao J, Ross CA, Dawson VL*, Dawson TM*. Parkin ubiquitinates the alpha-synuclein-interacting protein, synphilin-1: implications for Lewy-body formation in Parkinson disease. Nat Med. 2001 Oct;7(10):1144-50. doi: 10.1038/nm1001-1144. PMID: 11590439. 

  • Chung KK, Thomas B, Li X, Pletnikova O, Troncoso JC, Marsh L, Dawson VL*, Dawson TM*. S-nitrosylation of parkin regulates ubiquitination and compromises parkin's protective function. Science. 2004 May 28;304(5675):1328-31. doi: 10.1126/science.1093891. Epub 2004 Apr 22. PMID: 15105460. 

LRRK2 Kinase Activity and Neurodegeneration 

  • West AB, Moore DJ, Biskup S, Bugayenko A, Smith WW, Ross CA, Dawson VL*, Dawson TM*. Parkinson's disease-associated mutations in leucine-rich repeat kinase 2 augment kinase activity. Proc Natl Acad Sci U S A. 2005 Nov 15;102(46):16842-7. doi: 10.1073/pnas.0507360102. Epub 2005 Nov 3. PMID: 16269541; PMCID: PMC1283829. *Equal Contributions. 

  • Smith WW, Pei Z, Jiang H, Dawson VL*, Dawson TM*, Ross CA. Kinase activity of mutant LRRK2 mediates neuronal toxicity. Nat Neurosci. 2006 Oct;9(10):1231-3. doi: 10.1038/nn1776. Epub 2006 Sep 17. PMID: 16980962.  

  • 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*. Inhibitors of leucine-rich repeat kinase-2 protect against models of Parkinson's disease. Nat Med. 2010 Sep;16(9):998-1000. doi: 10.1038/nm.2199. Epub 2010 Aug 22. PMID: 20729864; PMCID: PMC2935926.  

  • Martin I, Kim JW, Lee BD, Kang HC, Xu JC, Jia H, Stankowski J, Kim MS, Zhong J, Kumar M, Andrabi SA, Xiong Y, Dickson DW, Wszolek ZK, Pandey A, Dawson TM*, Dawson VL*. Ribosomal protein s15 phosphorylation mediates LRRK2 neurodegeneration in Parkinson's disease. Cell. 2014 Apr 10;157(2):472-485. doi: 10.1016/j.cell.2014.01.064. PMID: 24725412; PMCID: PMC4040530.  

PAR Signaling in Cell Death Pathways 

  • 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*. Poly(ADP-ribose) (PAR) polymer is a death signal. Proc Natl Acad Sci U S A. 2006 Nov 28;103(48):18308-13. doi: 10.1073/pnas.0606526103. Epub 2006 Nov 20. PMID: 17116882; PMCID: PMC1838747. 

  • Yu SW, Andrabi SA, Wang H, Kim NS, Poirier GG, Dawson TM*, Dawson VL*. Apoptosis-inducing factor mediates poly(ADP-ribose) (PAR) polymer-induced cell death. Proc Natl Acad Sci U S A. 2006 Nov 28;103(48):18314-9. doi: 10.1073/pnas.0606528103. Epub 2006 Nov 20. PMID: 17116881; PMCID: PMC1838748.*Co-Senior and Corresponding Authors. 

  • Andrabi SA, Umanah GK, Chang C, Stevens DA, Karuppagounder SS, Gagné JP, Poirier GG, Dawson VL*, Dawson TM*. Poly(ADP-ribose) polymerase-dependent energy depletion occurs through inhibition of glycolysis. Proc Natl Acad Sci U S A. 2014 Jul 15;111(28):10209-14. doi: 10.1073/pnas.1405158111. Epub 2014 Jul 1. PMID: 24987120; PMCID: PMC4104885. *Equal Contributions. 

  • Wang Y, Kim NS, Haince JF, Kang HC, David KK, Andrabi SA, Poirier GG, Dawson VL*, Dawson TM*. Poly(ADP-ribose) (PAR) binding to apoptosis-inducing factor is critical for PAR polymerase-1-dependent cell death (parthanatos). Sci Signal. 2011 Apr 5;4(167):ra20. doi: 10.1126/scisignal.2000902. PMID: 21467298; PMCID: PMC3086524.  

Iduna and PARP in Neuroprotection 

  • Andrabi SA, Kang HC, Haince JF, Lee YI, Zhang J, Chi Z, West AB, Koehler RC, Poirier GG, Dawson TM*, Dawson VL*. Iduna protects the brain from glutamate excitotoxicity and stroke by interfering with poly(ADP-ribose) polymer-induced cell death. Nat Med. 2011 Jun;17(6):692-9. doi: 10.1038/nm.2387. Epub 2011 May 22. PMID: 21602803; PMCID: PMC3709257. *Co-corresponding and senior authors. 

  • Kang HC, Lee YI, Shin JH, Andrabi SA, Chi Z, Gagné JP, Lee Y, Ko HS, Lee BD, Poirier GG, Dawson VL*, Dawson TM*. Iduna is a poly(ADP-ribose) (PAR)-dependent E3 ubiquitin ligase that regulates DNA damage. Proc Natl Acad Sci U S A. 2011 Aug 23;108(34):14103-8. doi: 10.1073/pnas.1108799108. Epub 2011 Aug 8. PMID: 21825151; PMCID: PMC3161609. * Equal Contributions. 

c-Abl Signaling in Parkinson's Pathogenesis 

  • Karuppagounder SS, Wang H, Kelly T, Rush R, Nguyen R, Bisen S, Yamashita Y, Sloan N, Dang B, Sigmon A, Lee HW, Marino Lee S, Watkins L, Kim E, Brahmachari S, Kumar M, Werner MH, Dawson TM*, Dawson VL*. The c-Abl inhibitor IkT-148009 suppresses neurodegeneration in mouse models of heritable and sporadic Parkinson's disease. Sci Transl Med. 2023 Jan 18;15(679):eabp9352. doi: 10.1126/scitranslmed.abp9352. Epub 2023 Jan 18. PMID: 36652533. 

  • Ko HS, Lee Y, Shin JH, Karuppagounder SS, Gadad BS, Koleske AJ, Pletnikova O, Troncoso JC, Dawson VL*, Dawson TM*. Phosphorylation by the c-Abl protein tyrosine kinase inhibits parkin's ubiquitination and protective function. Proc Natl Acad Sci U S A. 2010 Sep 21;107(38):16691-6. doi: 10.1073/pnas.1006083107. Epub 2010 Sep 7. PMID: 20823226; PMCID: PMC2944759. * Equal Contributions. 

  • Brahmachari S, Ge P, Lee SH, Kim D, Karuppagounder SS, Kumar M, Mao X, Shin JH, Lee Y, Pletnikova O, Troncoso JC, Dawson VL*, Dawson TM*, Ko HS. Activation of tyrosine kinase c-Abl contributes to α-synuclein-induced neurodegeneration. J Clin Invest. 2016 Aug 1;126(8):2970-88. doi: 10.1172/JCI85456. Epub 2016 Jun 27. PMID: 27348587; PMCID: PMC4966315. *Equal Contributions. 

PARIS-Mediated Pathways in Parkinson's Disease 

  • Jo A, Lee Y, Kam TI, Kang SU, Neifert S, Karuppagounder SS, Khang R, Kang H, Park H, Chou SC, Oh S, Jiang H, Swing DA, Ham S, Pirooznia S, Umanah GKE, Mao X, Kumar M, Ko HS, Kang HC, Lee BD, Lee YI, Andrabi SA, Park CH, Lee JY, Kim H, Kim H, Kim H, Cho JW, Paek SH, Na CH, Tessarollo L, Dawson VL*, Dawson TM*, Shin JH. PARIS farnesylation prevents neurodegeneration in models of Parkinson's disease. Sci Transl Med. 2021 Jul 28;13(604):eaax8891. doi: 10.1126/scitranslmed.aax8891. PMID: 34321320; PMCID: PMC9990146.  

  • Shin JH, Ko HS, Kang H, Lee Y, Lee YI, Pletinkova O, Troconso JC, Dawson VL*, Dawson TM*. PARIS (ZNF746) repression of PGC-1α contributes to neurodegeneration in Parkinson's disease. Cell. 2011 Mar 4;144(5):689-702. doi: 10.1016/j.cell.2011.02.010. PMID: 21376232; PMCID: PMC3063894.  

  • Lee Y, Stevens DA, Kang SU, Jiang H, Lee YI, Ko HS, Scarffe LA, Umanah GE, Kang H, Ham S, Kam TI, Allen K, Brahmachari S, Kim JW, Neifert S, Yun SP, Fiesel FC, Springer W, Dawson VL*, Shin JH, Dawson TM*. PINK1 Primes Parkin-Mediated Ubiquitination of PARIS in Dopaminergic Neuronal Survival. Cell Rep. 2017 Jan 24;18(4):918-932. doi: 10.1016/j.celrep.2016.12.090. PMID: 28122242; PMCID: PMC5312976. 

  • Brahmachari S, Lee S, Kim S, Yuan C, Karuppagounder SS, Ge P, Shi R, Kim EJ, Liu A, Kim D, Quintin S, Jiang H, Kumar M, Yun SP, Kam TI, Mao X, Lee Y, Swing DA, Tessarollo L, Ko HS, Dawson VL*, Dawson TM*. Parkin interacting substrate zinc finger protein 746 is a pathological mediator in Parkinson's disease. Brain. 2019 Aug 1;142(8):2380-2401. doi: 10.1093/brain/awz172. PMID: 31237944; PMCID: PMC6658849. *Equal Contributions. 

AIMP2-Induced PARP Activation in Neuronal Loss 

  • 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*. Parthanatos mediates AIMP2-activated age-dependent dopaminergic neuronal loss. Nat Neurosci. 2013 Oct;16(10):1392-400. doi: 10.1038/nn.3500. Epub 2013 Aug 25. Erratum in: Nat Neurosci. 2015 Dec;18(12):1861. PMID: 23974709; PMCID: PMC3785563. *Equal Contributions. 

MIF Nuclease and Neuroprotection in PD 

  • Park H, Kam TI, Peng H, Chou SC, Mehrabani-Tabari AA, Song JJ, Yin X, Karuppagounder SS, Umanah GK, Rao AVS, Choi Y, Aggarwal A, Chang S, Kim H, Byun J, Liu JO, Dawson TM*, Dawson VL*. PAAN/MIF nuclease inhibition prevents neurodegeneration in Parkinson's disease. Cell. 2022 May 26;185(11):1943-1959.e21. doi: 10.1016/j.cell.2022.04.020. Epub 2022 May 10. PMID: 35545089; PMCID: PMC9149120.  

Animation by I-Hsun Wu

  • 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*. A nuclease that mediates cell death induced by DNA damage and poly(ADP-ribose) polymerase-1. Science. 2016 Oct 7;354(6308):aad6872. doi: 10.1126/science.aad6872. PMID: 27846469; PMCID: PMC5134926. *Equal Contributions. 

LAG3 in Parkinson's Disease 

Animation by I-Hsun Wu

  • Mao X, Ou MT, Karuppagounder SS, Kam TI, Yin X, Xiong Y, Ge P, Umanah GE, Brahmachari S, Shin JH, Kang HC, Zhang J, Xu J, Chen R, Park H, Andrabi SA, Kang SU, Gonçalves RA, Liang Y, Zhang S, Qi C, Lam S, Keiler JA, Tyson J, Kim D, Panicker N, Yun SP, Workman CJ, Vignali DA, Dawson VL*, Ko HS, Dawson TM*. Pathological α-synuclein transmission initiated by binding lymphocyte-activation gene 3. Science. 2016 Sep 30;353(6307):aah3374. doi: 10.1126/science.aah3374. PMID: 27708076; PMCID: PMC5510615. *Equal Contributions. 

Neurotoxic Reactive Astrocytes 

  • Park JS, Kam TI, Lee S, Park H, Oh Y, Kwon SH, Song JJ, Kim D, Kim H, Jhaldiyal A, Na DH, Lee KC, Park EJ, Pomper MG, Pletnikova O, Troncoso JC, Ko HS, Dawson VL*, Dawson TM*, Lee S. Blocking microglial activation of reactive astrocytes is neuroprotective in models of Alzheimer's disease. Acta Neuropathol Commun. 2021 Apr 26;9(1):78. doi: 10.1186/s40478-021-01180-z. PMID: 33902708; PMCID: PMC8074239.

  • Liddelow SA, Guttenplan KA, Clarke LE, Bennett FC, Bohlen CJ, Schirmer L, Bennett ML, Münch AE, Chung WS, Peterson TC, Wilton DK, Frouin A, Napier BA, Panicker N, Kumar M, Buckwalter MS, Rowitch DH, Dawson VL*, Dawson TM*, Stevens B, Barres BA. Neurotoxic reactive astrocytes are induced by activated microglia. Nature. 2017 Jan 26;541(7638):481-487. doi: 10.1038/nature21029. Epub 2017 Jan 18. PMID: 28099414; PMCID: PMC5404890.  

  • Yun SP, Kam TI, Panicker N, Kim S, Oh Y, Park JS, Kwon SH, Park YJ, Karuppagounder SS, Park H, Kim S, Oh N, Kim NA, Lee S, Brahmachari S, Mao X, Lee JH, Kumar M, An D, Kang SU, Lee Y, Lee KC, Na DH, Kim D, Lee SH, Roschke VV, Liddelow SA, Mari Z, Barres BA, Dawson VL*, Lee S, Dawson TM*, Ko HS. Block of A1 astrocyte conversion by microglia is neuroprotective in models of Parkinson's disease. Nat Med. 2018 Jul;24(7):931-938. doi: 10.1038/s41591-018-0051-5. Epub 2018 Jun 11. PMID: 29892066; PMCID: PMC6039259. *Equal Contributions. 

PAR Drive PD Pathogenesis 

  • Kam TI, Mao X, Park H, Chou SC, Karuppagounder SS, Umanah GE, Yun SP, Brahmachari S, Panicker N, Chen R, Andrabi SA, Qi C, Poirier GG, Pletnikova O, Troncoso JC, Bekris LM, Leverenz JB, Pantelyat A, Ko HS, Rosenthal LS, Dawson TM*, Dawson VL*. Poly(ADP-ribose) drives pathologic α-synuclein neurodegeneration in Parkinson's disease. Science. 2018 Nov 2;362(6414):eaat8407. doi: 10.1126/science.aat8407. PMID: 30385548; PMCID: PMC6431793. *Equal Contributions. 

PD Pathways

Animation by I-Hsun Wu