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 Immunity and PD

• Panicker, N., T.-I. Kam, H. Wang, S. Neifert, S.-C. Chou, M. Kumar, S. Brahmachari, A. Jhaldiyal, J.T. Hinkle, F. Akkentli, X. Mao, E. Xu, S.S. Karuppagounder, E.T. Hsu, S.-U. Kang, O. Pletnikova, J. Troncoso, V.L. Dawson*, T.M. Dawson*. “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.

• Hinkle, J.T., J. Patel, N. Panicker, S.S. Karuppagounder, D. Biswas, B. Belingnon, R. Chen, S. Brahmachari, O. Pletnikova, J.C. Troncoso, V.L. Dawson* and T.M. Dawson* “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 (2022).

Gut to Brain transmission of pathologic a-synuclein

• Kim, S., S.H. Kwon, T.-I. Kam, N. Panicker, S.S. Karuppagounder, S. Lee, J. H. Lee1, W.R. Kim, M. Kook, C.A. Foss, C. Shen, S. Kulkarni, P.J. Pasricha, G. Lee, M.G. Pomper, V.L. Dawson*, *T.M. Dawson, and *H.S. Ko. “Transneuronal Propagation of Pathologic α-Synuclein from the Gut to the Brain Models Parkinson’s disease.” Neuron, 103:627-641.e7 (2019) DOI:10.1016/j.neuron.2019.05.035. PMID: 31255487, PMCID: PMC6706297, DOI: 10.1016/j.neuron.2019.05.035. *Equal Contributions.

NO is Toxic

• Dawson, V.L., T.M. Dawson, E.D. London, D.S. Bredt, and S.H. Snyder. “Nitric Oxide Mediates Glutamate Toxicity in Primary Cortical Cultures.” PMID: 1648740, DOI: 10.1073/pnas.88.14.6368. Proc. Natl. Acad. Sci. USA 88: 6368-6371 (1991). (Citations: 2599)

• Dawson, T.M., D.S. Bredt, M. Fotuhi, P.M. Hwang and S.H. Snyder.  "Nitric Oxide Synthase and Neuronal NADPH Diaphorase are Identical in Brain and Peripheral Tissue." Proc. Natl. Acad. Sci., U.S.A., 88:7797-7801 (1991), PMID: 1715581, PMCID: PMC52390, doi: 10.1073/pnas.88.17.7797.

• Adamson, D.C., B. Wildemann, M. Sasaki, J.D. Glass, J.C. McArthur, V.I. Christov, T.M. Dawson* and V.L. Dawson*.  “Immunologic NO Synthase:  Elevation in Severe AIDS Dementia and Induction by HIV-1 gp41,.” Science,  274: 1917-1921 (1996), PMID: 8943206, DOI: 10.1126/science.274.5294.1917. *Equal Contributions.

• Przedborski, S., V. Jackson-Lewis, R. Yokohama, T. Shibata, V.L. Dawson* and T.M Dawson*.  “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: 4565-4571 (1996), PMID: 8643444, PMCID: PMC39317, https://doi.org/10.1073/pnas.93.10.4565. *Equal Contributions.

• Liberatore, G.T., V. Jackson-Lewis,  S. Vukosavic, A.S. Mandir,M. Vila,  G. McAuliffe, V.L. Dawson, T.M. Dawson, S. Przedborski.  “Inducible Nitric Oxide Stimulates Dopaminergic Neurodegeneration in the MPTP Model of Parkinson Disease.”  Nature Medicine,  12:1403-1409, (1999), PMID: 10581083, DOI: 10.1038/70978.

PARP is a death effector of NO

• Zhang, J., V.L. Dawson, T.M. Dawson and S.H. Snyder.  "Nitric Oxide Activation of Poly (ADP-Ribose) Synthetase in Neurotoxicity."  Science, 263:687-689 (1994), PMID: 8080500, DOI: 10.1126/science.8080500.

• Eliasson, M.J.L., D. Sampei, A.S. Mandir, P.D. Hurn, R.J. Traystman, J. Bao, A. Pieper,  Z.-Q. Wang, T.M. Dawson*, S.H. Snyder* and V.L. Dawson*.  “Poly (ADP-Ribose) Polymerase Gene Disruption Renders Mice Resistant to Cerebral Ischemia.”  Nature Medicine, 3: 1089-1095 (1997), PMID: 9334719, DOI: 10.1038/nm1097-1089. *Equal Contributions.

• Mandir, A.S., S. Przedborski, V. Jackson-Lewis, Z.-Q. Wang, C. M. Simbulan-Rosenthal, M. E. Smulson, B.E. Hoffman, D. B. Guastella, V.L. Dawson* and T.M. Dawson*.  “Poly (ADP-Ribose) Polymerase Activation Mediates MPTP-Induced Parkinsonism.”  Proc. Natl. Acad. Sci., U.S.A. 96: 5774-5779 (1999), PMID: 10318960, PMCID: PMC21936, DOI: 10.1073/pnas.96.10.5774. *Equal Contributions.

• 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. PubMed PMID: 27053772; PubMed Central PMCID: PMC5595216, DOI: 10.1126/scitranslmed.aad0623.

AIF is a death effector of PARP

• Yu, S.W., H. Wang, M.F. Poitras, C. Coombs, W.J. Bowers, H.J. Federoff, G.G. Poirier, T.M. Dawson, V.L. Dawson. “Mediation of Poly(ADP-Ribose) Polymerase-1 Dependent Cell Death by Apoptosis Inducing Factor,” PMID: 12114629, DOI: 10.1126/science.1072221. Science 297:259-263 (2002).

PARKIN is an E3 Ligase

• Zhang, Y., J. Gao, K.K.K. Chung, H. Huang, V.L. Dawson* and T.M. Dawson*.  "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., 97:13354-13359 (2000), PMID: 11078524, PMCID: PMC27228, DOI: 10.1073/pnas.240347797. *Equal Contributions.

• Chung, K.K.K, Y. Zhang, K. L. Lim, Y. Tanaka, H. Huang, J. Gao, C. A. Ross, V. L. Dawson* and T. M. Dawson*. "Parkin Ubiquitinates the a-Synuclein-Interacting Protein, Synphilin-1: Implications for Lewy Body Formation in Parkinson Disease." Nature Medicine, 7:1144-1150 (2001), PMID: 11590439, DOI: 10.1038/nm1001-1144. *Equal Contributions.

• Chung, K.K.K., B. Thomas, X. Li, O. Pletnikova, J.C. Troncoso, L. Marsh, V. L. Dawson* and T.M. Dawson*.  “S-Nitrosylation of Parkin Regulates Ubiquitination and Compromises Parkin’s Protective Function.” Science, 304:1328-1331 (2004). PMID:15105460; DOI: 10.1126/science.1093891. *Equal Contributions.

LRRK2 is a kinase and neurodegeneration is linked to the kinase activity

• West, A., D. Moore, A. Bugayenko, S. Biskup, W.W. Smith, C.A. Ross, V. L. Dawson* and T.M. Dawson*. “ Parkinson’s Disease Associated Mutations in Leucine Rich Repeat Kinase 2 Augment Kinase Activity.” Proc. Natl. Acad. Sci. U.S.A., 102:16842-16847 (2005), PMID: 16269541, PMCID: PMC1283829, DOI: 10.1073/pnas.0507360102. *Equal Contributions.

• Smith, W.W. Z. Pei, H. Jiang, V. L. Dawson, T.M. Dawson, C.A. Ross.  “Kinase Activity of Mutant LRRK2 Mediates Neuronal Toxicity.”  Nature Neuroscience, 9:1231-3. Epub 2006 Sep 17. (2006), PMID: 16980962, DOI: 10.1038/nn1776.

• 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. PubMed PMID: 20729864; PubMed Central PMCID: PMC2935926; DOI: 10.1038/nm.2199.

• Martin, I., J.W. Kim, B.D Lee, H.C. Kang, J.-C. Xu., H. Jia, J. Stankowski, M.-S. Kim, J. Zhong, M. Kumar, S. Andrabi, A Pandey, T.M. Dawson*, V.L. Dawson*. “Ribosomal protein s15 phosphorylation mediates LRRK2 neurodegeneration in Parkinson’s disease” Cell, 157:472-485 (2014). 10.1016/j.cell.2014.01.064 *Co-corresponding and senior authors. PMID: 24725412, PMCID: PMC4040530.

PAR is a death signal

• Andrabi, S., N.S. Kim, S.W. Yu, H. Wang, D. Koh, M. Sasaki, J.A. Klaus, T. Otsuka, Z. Zhang, R.C. Koehler, P. Hurn, G.G. Poirier, V.L. Dawson* and T.M. Dawson*. “Poly (ADP-ribose) (PAR) Polymer is a Death Signal.” Proc. Natl. Acad. Sci. U.S.A. [Epub Nov. 20, 2006, https://doi.org/10.1073/pnas.0606526103] 103: 18308–18313  (2006). PMID:17116882, PMCID: PMC1838747. *Co-Senior and Corresponding Authors.

• Yu, S.W., S.A. Andrabi, H. Wang, N.S. Kim, G.G. Poirier, T.M. Dawson* and V.L. Dawson*. “Apoptosis Inducing Factor (AIF) Mediates Poly (ADP-ribose) (PAR) Polymer Induced Cell Death.”  Proc. Natl. Acad. Sci. U.S.A. [Epub Nov. 20, 2006, 10.1073/pnas.0606528103] 103: 18314–18319 (2006), PMID:17116881, PMCID: PMC1838748. https://doi.org/10.1073/pnas.060652810 *Co-Senior and Corresponding Authors.

• Andrabi, S.A., G.K.E. Umanah, C. Chang, D.A. Stevens, S. Karupagounder, J.-P. Gagne, G.P. Poirier, V.L. Dawson*, T.M. Dawson*.  “Poly (ADP-Ribose) Polymerase Dependent Energy Depletion Occurs Through Inhibition of Glycolysis.” Proc. Natl. Acad. Sci., U.S.A., 111:10209-14 (2014). DOI: 10.1073/pnas.1405158111, PMID: 25174890, PMCID: PMC4455551. *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).”POl Sci Signal. 2011 Apr 5;4(167):ra20. PubMed PMID: 21467298; 10.1126/scisignal.2000902; PubMed Central PMCID: PMC3086524.

Iduna

• 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. https://doi.org/10.1038/nm.2387. Epub 2011 May 22. PMID: 21602803; PMCID: PMC3709257. *Co-corresponding and senior authors.

• Kang, H.C., Y.-I. Lee, J.-H. Shin, S. Andrabi, Z. Chi, J.-P. Gagne, Y. Lee, H.S. Ko, B.D. Lee, G.G. Poirier, V.L. Dawson*, T.M. Dawson*. “Iduna is a Poly (ADP-Ribose) (PAR)-Dependent E3 Ubiquitin Ligase that Regulates DNA Damage.” Proc. Natl. Acad. Sci. U.S.A., DOI:10.1073/pnas.1108799108 (2011). PMID: 21825151, PMCID: PMC3161609  * Equal Contributions.

c-Abl is overactive in PD

• Karuppagounder, S.S., H. Wang, T. Kelly, R. Rush, R. Nguyen, S. Bisen, Y. Yamashita, N. Sloan, B. Dang, A. Sigmon, H.W. Lee, S.M. Lee, L. Watkins, E. Kim, S. Brahmachari, M. Kumar, M.H. Werner*, T.M. Dawson* and V.L. Dawson*. “The c-Abl inhibitor IkT-148009 therapeutically suppresses neurodegeneration in models of heritable and sporadic Parkinson’s Disease.” Science Translational Medicine, 18 Jan 2023 Vol 15, Issue 679, DOI: 10.1126/scitranslmed.abp9352 (2023)

• Ko, H.S., Y. Lee, J.-H. Shin, S.S. Karuppagounder, B.S. Gadad, A.J. Koleske, O. Pletnikova, J.C. Troncoso, V.L. Dawson*, T.M. Dawson*. Phosphorylation by the c-Abl Protein Tyrosine Kinase Inhibits Parkin’s Ubiquitination and Protective Function.” Proc. Natl. Acad. Sci. U.S.A., published ahead of print September 7, 2010, doi:10.1073/pnas.1006083107; 107:16691-16696 (2010) PMID: 20823226, PMCID: PMC2944759. * Equal Contributions.

• Brahmachari, S., P.Ge, S.H. Lee, D. Kim, S.S. Karuppagounder, M. Kumar, X. Mao, Y. Lee, O. Pletnikova, J.C. Troncoso, V.L. Dawson*, T.M.Dawson* and H.S. Ko*. “Activation of tyrosine kinase c-Abl contributes to a-Synuclein-Induced Neurodegeneration.” J. Clinical Investigation, 26:2970-2988.  doi: 10.1172/JCI85456. (2016). PMID: 27348587, PMCID: PMC4966315. *Both authors contributed equally. *Equal Contributions.

PARIS

• Jo, A., Y. Lee, H. Jiang, T.-I. Kam, S.-U. Kang, H. Jiang, R. Khang, H. Kang, S.S. Karuppagounder, D.A. Swing, S. Ham, S. Pirooznia, S. Neifert, G.K.E. Umanah, X. Mao, M. Kumar, H. Park, H.S. Ko, H.C. Kang, B.D. Lee, Y.-I. Lee, S.A. Andrabi, C-.H. Park, J.-Y. Lee, H. Kim, H. Kim, H. Kim, J.W. Cho, S.H. Paek, L. Tessarollo, V.L. Dawson, *T.M. Dawson and *J.-H. Shin. “PARIS Farnesylation prevents neurodegeneration in models of Parkinson’s disease.” Science Translational Medicine., 2021 Jul 28;13(604):eaax8891. doi: 10.1126/scitranslmed.aax8891. PMID: 34321320 (2021)

• Shin, J.-H., H.S. Ko, H.C. Kang, Y. Lee, Y.-I. Lee, O. Pletinkova, J.C. Troncoso, V.L. Dawson* and T.M. Dawson*. “PARIS (ZNF746) Repression of PGC-1α Contributes to Neurodegeneration in Parkinson’s Disease.” Cell, 144:689-702 (2011), PMID: 21376232, PMCID: PMC3063894. (Featured Article). * Equal Contributions

• 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., C. Yuan, S.S. Karuppagounder, P.Ge, D. Kim, A. Liu, H. Jiang, X. Mao, Y. Lee, D.A. Swing, L. Tessarollo, H.S. Ko, *V.L. Dawson* and T.M. Dawson*. “Parkin interacting substrate zinc finger protein 746 is a pathologic mediator in Parkinson’s disease.” Brain, 142:2380-2401 (2019) DOI: 10.1093/brain/awz172 PMID: 31237944, PMCID: PMC6658849. *Equal Contributions.

AIMP2 Activates PARP

• Lee, Y., Karuppagounder, S., Shin, JH., Lee, YI., Ko, HS., Swing, D., Jiang, H., Kang, SU., Lee, BD., Kang, HC., Kim, D., Tessarollo, L., Dawson, VL., Dawson, TD. “Parthanatos mediates AIMP2-activated age-dependent dopaminergic neuronal loss.” Nat Neurosci 16, 1392–1400 (2013). https://doi.org/10.1038/nn.3500. *Equal Contributions.

MIF Nuclease

• Park, H.,  T.-I. Kam, H. Peng , A.A. Mehrabani-Tabari,  S.-C. Chou, S.S. Karuppagounder, G.K. Umanah, A.V. S. Rao, S. Chang, H. Kim, J. Byun, J.O. Liu, T.M. Dawson*, V.L. Dawson* “PAAN/MIF Nuclease Inhibition Prevents Neurodegeneration in Parkinson’s Disease,” *Equal Contributions and Co-corresponding authors., Cell., 2022 May 26;185(11):1943-1959.e21. doi: 10.1016/j.cell.2022.04.020. Epub 2022 May 10 PMID: 35545089

• Wang, Y., R. An, G.K. Umanah, H. Park, K. Nambiar, S.M. Eacker, B.W. Kim, L. Bao, M.M. Harraz, C. Chang, R. Chen, J.E. Wang, T.-I. Kam, J.S. Jeong, Z. Xie, S. Neifert, J. Qian, S.A. Andrabi, S. Blackshaw, H. Zhu, H. Song, G. Ming, V.L. Dawson*, T.M. Dawson* “A Nuclease that Mediates Cell Death induced by DNA Damage and Poly(ADP-ribose) Polymerase-1.” Science, 354, aad6872 (2016). DOI: 10.1126/science.aad6872.  (2016). PMCID: PMID:27846469, PMC5134926. *Equal Contributions.

LAG3

• Mao, X., T. Ou, S.S. Karuppagounder, T.-I. Kam, X. Yin, Y. Xiong, P. Ge, G.E. Umanah, S. Brahmachari, J.-H. Shin, H.C. Kang, J. Zhang, J. Xu, R. Chen, H. Park, S.A. Andrabi, S.U. Kang, R.A. Goncalves, Y. Liang, S. Zhang, C. Qi, S. Lam, J.A. Keiler, J. Tyson, D. Kim, N. Panicker, S.P. Yun, C.J. Workman, D.A.A. Vignali, V.L. Dawson*, H.S. Ko*, T.M. Dawson*. “Pathological a-synuclein transmission initiated by binding lymphocyte-activation gene 3 receptor.” Science 353, aah3374 (2016). DOI: 10.1126/science.aah3374,  PMID: 27708076, PMCID: PMC5510615. *Equal Contributions.

Neurotoxic Reactive Astrocytes

• Park, J.-S., T.-I. Kam, H. Park, Y. Oh, S. Lee, D. Kim, D.H. Na, H. Kim, K.C. Lee, E.J. Park, M.G. Pomper, O. Pletnikova, J.C. Troncoso, H.S. Ko, V.L. Dawson, *T.M. Dawson, *S. Lee. "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 (2021).

• Liddelow, S.A., K.A. Guttenplan, L.E. Clarke, F.C. Bennett, C.J. Bohlen, L. Schirmer, M.L. Bennett, A.E. Münch, W.-S. Chung, T.C. Peterson, D.K. Wilton, A. Frouin, B.A. Napier, N. Panicker, M. Kumar, M.S. Buckwalter, D.H. Rowitch, V.L. Dawson, T.M. Dawson, B. Stevens, B.A. Barres “Neurotoxic reactive astrocytes are induced by activate microglia” Nature, Jan 26;541(7638):481-487. doi: 10.1038/nature21029. (2017) PMID:28099414, PMCID: PMC5404890.

• Yun, S.P., T.-I. Kam, N. Panicker, S.M. Kim, Y. Oh, J.-S. Park, S.-H. Kwon, Y.J. Park, S.S. Karuppagounder, H. Park, S. Kim, N. Oh, N.A. Kim, S. Lee, S. Brahmachari, X. Mao, J.H. Lee, M. Kumar, D. An, S.-U. Kang, Y. Lee, K.C. Lee, D.H. Na, D. Kim, S.H. Lee, S.A. Liddelow, Z. Mari, B.A. Barres, V.L. Dawson*, S. Lee*, *T.M. Dawson and *H. Ko “Block of A1 astrocyte conversion is neuroprotective in models of Parkinson’s disease.” Nature Medicine, Jul;24(7):931-938. doi: 10.1038/s41591-018-0051-5. Epub 2018 Jun 11. (2018) PMID: 29892066, PMCID: PMC6039259. *Equal Contributions.

PAR Drive PD Pathogenesis

• Kam, T.-I., X. Mao, H. Park, S.S. Karuppagounder, S.-C. Chou, G.E. Umanah, S. Brahmachari, S.P. Yun, N. Panicker, R. Chen, S.A. Andrabi, C. Qi, G.G. Poirier, O. Pletnikova, J.C. Troncoso, L.M. Bekris, J.B. Leverenz, A.Pantelyat, H.S. Ko, L.S. Rosenthal, T.M. Dawson* and V.L. Dawson* “Poly (ADP-ribose) Drives Pathologic a-Synuclein Neurodegeneration.” *Both authors contributed equally, Science 362, eaat8407 (2018). DOI: 10.1126/science.aat8407, PMID: 30385548, PMCID: PMC6431793. *Equal Contributions.