Saurav Brahmachari,1,2,3 Preston Ge,1,2,3 Su Hyun Lee,1,2 Donghoon Kim,1,2,4 Senthilkumar S. Karuppagounder,1,2,3 Manoj Kumar,1,2,3 Xiaobo Mao,1,2,3 Yunjong Lee,1,2,3 Olga Pletnikova,5 Juan C. Troncoso,2,5 Valina L. Dawson,1,2,3,6,7 Ted M. Dawson,1,2,3,7,8,* and Han Seok Ko1,2,4,*
1Neuroregeneration and Stem Cell Programs, Institute for Cell Engineering, and 2Department of Neurology, The Johns Hopkins University School of Medicine, Baltimore, Maryland, USA. 3Adrienne Helis Malvin Medical Research Foundation, New Orleans, Louisiana, USA. 4Diana Helis Henry Medical Research Foundation, New Orleans, Louisiana, USA. 5Department of Pathology, Division of Neuropathology, 6Department of Physiology, 7Solomon H. Snyder Department of Neuroscience, and 8Department of Pharmacology and Molecular Sciences, The Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.
*Address correspondence to: Han Seok Ko, Neuroregeneration and Stem Cell Programs, Institute for Cell Engineering, Johns Hopkins University School of Medicine, 733 North Broadway, Suite 751A,
Baltimore, Maryland 21205, USA.; Or to: Ted Dawson, Neuroregeneration and Stem Cell Programs, Institute for Cell Engineering, Johns Hopkins University School of Medicine, 733 North Broadway, Suite 731, Baltimore, Maryland 21205, USA.
Aggregation of α-synuclein contributes to the formation of Lewy bodies and neurites, the pathologic hallmarks of Parkinson disease (PD) and α-synucleinopathies. Although a number of human mutations have been identified in familial PD, the mechanisms that promote α-synuclein accumulation and toxicity are poorly understood. Here, we report that hyperactivity of the nonreceptor tyrosine kinase c-Abl critically regulates α-synuclein-induced neuropathology. In mice expressing a human α-synucleinopathy-associated mutation (hA53Tα-syn mice), deletion of the gene encoding c-Abl reduced α-synuclein aggregation, neuropathology, and neurobehavioral deficits. Conversely, overexpression of constitutively active c-Abl in hA53Tα-syn mice accelerated α-synuclein aggregation, neuropathology, and neurobehavioral deficits. Moreover, c-Abl activation led to an age-dependent increase in phosphotyrosine 39 α-synuclein. In human postmortem samples, there was an accumulation of phosphotyrosine 39 α-synuclein in brain tissues and Lewy bodies of PD patients compared with age-matched controls. Furthermore, in vitro studies show that c-Abl phosphorylation of α-synuclein at tyrosine 39 enhances α-synuclein aggregation. Taken together, this work establishes a critical role for c-Abl in α-synuclein-induced neurodegeneration and demonstrates that selective inhibition of c-Abl may be neuroprotective. This study further indicates that phosphotyrosine 39 α-synuclein is a potential disease indicator for PD and related α-synucleinopathies.