Parkinson’s Disease Modification through Abl Kinase Inhibition: An Opportunity
November 2021
Milton H. Werner, PhD, and C. Warren Olanow, MD
Parkinson's Disease
Parkinson’s Disease
Viral-based rodent and nonhuman primate models of multiple system atrophy: Fidelity to the human disease
November 2020
David J. Marmion, Angela A. Rutkowski, Diptaman Chatterjee, Benjamin M. Hiller, Milton H. Werner, Erwan Bezard, Deniz Kirik, Thomas McCown, Steven J. Gray i, Jeffrey H. Kordower
Transneuronal Propagation of Pathologic α-Synuclein from the Gut to the Brain Models Parkinson’s disease
August 2020
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.
Parkin interacting substrate zinc finger protein 746 is a pathological mediator in Parkinson’s disease
August 2019
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.
Poly (ADP-ribose) Drives Pathologic α-Synuclein Neurodegeneration in Parkinson’s Disease.
May 2019
T. I. Kam, X. Mao, H. Park, S-C Chou, S. S. Karuppagounder, G. E. Umanah, S. P. Yun, S. Brahmachari, 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 alpha-Synuclein Neurodegeneration in Parkinson’s Disease, Science 362, pii: eaat8407. doi: 10.1126/science.aat8407, (2018).
Pathological α-synuclein Transmission Initiated by Binding Lymphocyte-activation Gene 3
September 2016
Mao, M. 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. Gonçalves, 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. Vignali, V. L. Dawson, H. S. Ko, T. M. Dawson. (2016) Pathological α-synuclein transmission initiated by binding lymphocyte-activation gene 3. Science353:aah374.
Pathological α-synuclein transmission initiated by binding lymphocyte-activation gene 3
September 2016
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. (2016) Pathological α-synuclein transmission initiated by binding lymphocyte-activation gene 3. Science. Sep 30;353(6307). pii: aah3374.
Nilotinib Effects in Parkinson’s Disease and Dementia with Lewy Bodies
July 2016
Pagan F, Hebron M, Valadez EH, Tores-Yaghi Y, Huang X, Mills RR, Wilmarth BM, Howard H, Dunn C, Carlson A, Lawler A, Rogers SL, Drew Falconer R, Ahn J, Li Z, Moussa C. (2016) Nilotinib Effects in Parkinson’s disease and Dementia with Lewy bodies. J Parkinsons Dis. 2016 Jul 11.
Nilotinib – Differentiating the Hope from the Hype
July 2016
Wyse RK, Brundin P, Sherer TB. (2016) Nilotinib – Differentiating the Hope from the Hype. J Parkinsons Dis. 2016 Jul 12.
Activation of Tyrosine Kinase c-Abl Contributes to α-synuclein-Induced Neurodegeneration
June 2016
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. (2016) Activation of tyrosine kinase c-Abl contributes to α-synuclein-induced neurodegeneration. J Clin Invest. 126:2970-88.
Targeting α-synuclein for Treatment of Parkinson’s Disease: Mechanistic and Therapeutic Considerations
August 2015
Dehay B, Bourdenx M, Gorry P, Przedborski S, Vila M, Hunot S, Singleton A, Olanow CW, Merchant KM, Bezard E, Petsko GA, Meissner WG. (2015) Targeting α-synuclein for treatment of Parkinson’s disease: mechanistic and therapeutic considerations. Lancet Neurol. 14:855-66.
c-Abl Phosphorylates Alpha-synuclein and Regulates its Degradation: Implication for Alpha-synuclein Clearance and Contribution to the Pathogenesis of Parkinson’s Disease
June 2014
Mahul-Mellier AL, Fauvet B, Gysbers A, Dikiy I, Oueslati A, Georgeon S, Lamontanara AJ, Bisquertt A, Eliezer D, Masliah E, Halliday G, Hantschel O, Lashuel HA. (2014) c-Abl phosphorylates alpha-synuclein and regulates its degradation: implication for alpha-synuclein clearance and contribution to the pathogenesis of Parkinson’s disease. Hum Mol Genet. 23:2858-79.
The c-Abl Inhibitor, Nilotinib, Protects Dopaminergic Neurons in a Preclinical Animal Model of Parkinson’s Disease
May 2014
Karuppagounder SS, Brahmachari S, Lee Y, Dawson VL, Dawson TM, Ko HS. (2014) The c-Abl inhibitor, nilotinib, protects dopaminergic neurons in a preclinical animal model of Parkinson’s disease. Sci Rep. 2014 May 2;4:4874.
Nilotinib Reverses Loss of Dopamine Neurons and Improves Motor Behavior Via Autophagic Degradation of Alpha-synuclein in Parkinson’s Disease Models
May 2013
Hebron ML, Lonskaya I, Moussa CE. (2013) Nilotinib reverses loss of dopamine neurons and improves motor behavior via autophagic degradation of alpha-synuclein in Parkinson’s disease models. Hum Mol Genet. 22:3315-28.
Neuroprotective Efficacy of a New Brain-penetrating C-Abl Inhibitor in a Murine Parkinson’s Disease Model
May 2013
Imam SZ, Trickler W, Kimura S, Binienda ZK, Paule MG, Slikker W, Jr., Li S, Clark RA, Ali SF. (2013) Neuroprotective efficacy of a new brain-penetrating C-Abl inhibitor in a murine Parkinson’s disease model. PLoS One. 8:e65129.
c-Abl in Neurodegenerative Disease
July 2011
Schlatterer SD, Acker CM, Davies P. (2011) c-Abl in neurodegenerative disease. J Mol Neurosci. 45:445-52.
Novel Regulation of Parkin Function Through c-Abl-mediated Tyrosine Phosphorylation: Implications for Parkinson’s Disease
January 2011
Imam SZ, Zhou Q, Yamamoto A, Valente AJ, Ali SF, Bains M, Roberts JL, Kahle PJ, Clark RA, Li S. (2011) Novel regulation of parkin function through c-Abl-mediated tyrosine phosphorylation: implications for Parkinson’s disease. J Neurosci. 31:157-63.
Phosphorylation By the c-Abl Protein Tyrosine Kinase Inhibits Parkin’s Ubiquitination and Protective Function
September 2010
Ko HS, Lee Y, Shin JH, Karuppagounder SS, Gadad BS, Koleske AJ, Pletnikova O, Troncoso JC, Dawson VL, Dawson TM. (2010) Phosphorylation by the c-Abl protein tyrosine kinase inhibits parkin’s ubiquitination and protective function. Proc Natl Acad Sci U S A. 107:16691-6.
Molecular Pathways of Neurodegeneration in Parkinson’s Disease
October 2003
Dawson TM, Dawson VL. Molecular pathways of neurodegeneration in Parkinson’s disease. (2003) Science. 302:819-22.
PML (Progressive Multifocal Leukoencephalopathy)
Natalizumab-treated Patients at High Risk for PML Persistently Excrete JC Polyomavirus
December 2016
Werner GA and Huang D (2016) Natalizumab-treated patients at high risk for PML persistently excrete JC polyomavirus. J Neurovirol. 2016 Dec;22(6):871-875.
Reassessing the Risk of Natalizumab-associated PML
August 2016
Berger JR, Fox RJ. (2016) Reassessing the risk of natalizumab-associated PML. J Neurovirol. 2016 Aug;22(4):533-5.
Anti-JC Virus Antibody Levels in Serum or Plasma Further Define Risk of Natalizumab-associated Progressive Multifocal Leukoencephalopathy
October 2014
Plavina T, Subramanyam M, Bloomgren G, Richman S, Pace A, Lee S, Schlain B, Campagnolo D, Belachew S, Ticho B. (2014) Anti-JC virus antibody levels in serum or plasma further define risk of natalizumab-associated progressive multifocal leukoencephalopathy. Ann. Neurol. 76, 802-812.
JC Virus in CD34 and CD19 Cells in Patients with Multiple Sclerosis Treated with Natalizumab
May 2014
Frohman EM, Monaco MC, Remington G, Ryschkewitsch C, Jensen PN, Johnson K, Perkins M, Liebner J, Greenberg B, Monson N, Frohman TC, Douek D, Major EO. (2014) JC virus in CD34 and CD19 cells in patients with multiple sclerosis treated with natalizumab. JAMA Neurol. 71:596 – 602.
Progressive Multifocal Leukoencephalopathy (PML) Development is Associated with Mutations in JC Virus Capsid Protein VP1 That Change its Receptor Specificity
July 2011
Gorelik L, Reid C, Testa M, Brickelmaier M, Bossolasco S, Pazzi A, Bestetti A, Carmillo P, Wilson E, McAuliffe M, Tonkin C, Carulli JP, Lugovskoy A, Lazzarin A, Sunyaev S, Simon K, Cinque P. (2011) Progressive multifocal leukoencephalopathy (PML) development is associated with mutations in JC virus capsid protein VP1 that change its receptor specificity. J Infect Dis. Jul 1;204(1):103-14.
Human polyoma viruses and disease with emphasis on clinical BK and JC.
April 2010
Gorelik L, Reid C, Testa M, Brickelmaier M, Bossolasco S, Pazzi A, Bestetti A, Carmillo P, Wilson E, McAuliffe M, Tonkin C, Carulli JP, Lugovskoy A, Lazzarin A, Sunyaev S, Simon K, Cinque P. (2011) Boothpur R and Brennan D. C. (2010) Human polyoma viruses and disease with emphasis on clinical BK and JC. J. Clin. Virol. Doi 10.1416/j.jcv.2009.12.006
Abl Family Tyrosine Kinases Regulate Sialylated Ganglioside Receptors for Polyomavirus
April 2010
Swimm AI, Bornmann W, Jiang M, Imperiale MJ, Lukacher AE, Kalman D (2010) Abl family tyrosine kinases regulate sialylated ganglioside receptors for polyomavirus. J. Virol. 84, 4243-4251.
Aligning Antimicrobial Drug Discovery with Complex and Redundant Host-pathogen Interactions
February 2009
Lebeis SL, Kalman D. (2009) Aligning antimicrobial drug discovery with complex and redundant host-pathogen interactions. Cell Host Microbe 5:114-22.
Other Applications in Infectious Disease
New Tricks for Old Dogs: Countering Antibiotic Resistance in Tuberculosis with Host-directed Therapeutics
February 2015
Hawn TR, Shah JA, Kalman D. (2015) New tricks for old dogs: countering antibiotic resistance in tuberculosis with host-directed therapeutics. Immunol Rev. Mar;264(1):344-62.
Productive Replication of Ebola Virus is Regulated By the c-Abl1 Tyrosine Kinase
February 2012
García M, Cooper A, Shi W, Bornmann W, Carrion R, Kalman D, Nabel GJ. (2012) Productive replication of Ebola virus is regulated by the c-Abl1 tyrosine kinase. Sci Transl Med. 4:123ra24.
Variola and Monkeypox Viruses Utilize Conserved Mechanisms of Virion Motility and Release that Depend on Abl and SRC Family Tyrosine Kinases
December 2010
Reeves PM, Smith SK, Olson VA, Thorne SH, Bornmann W, Damon IK, Kalman D. (2011) Variola and monkeypox viruses utilize conserved mechanisms of virion motility and release that depend on abl and SRC family tyrosine kinases. J Virol. 85(1):21-31.