title: Activation of tyrosine kinase c-Abl contributes to α-synuclein-induced neurodegeneration.
abstract: 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.
authors.forename: Saurav
authors.initials: S
authors.lastname: Brahmachari
authors.forename: Preston
authors.initials: P
authors.lastname: Ge
authors.forename: Su Hyun
authors.initials: SH
authors.lastname: Lee
authors.forename: Donghoon
authors.initials: D
authors.lastname: Kim
authors.forename: Senthilkumar S
authors.initials: SS
authors.lastname: Karuppagounder
authors.forename: Manoj
authors.initials: M
authors.lastname: Kumar
authors.forename: Xiaobo
authors.initials: X
authors.lastname: Mao
authors.forename: Joo Ho
authors.initials: JH
authors.lastname: Shin
authors.forename: Yunjong
authors.initials: Y
authors.lastname: Lee
authors.forename: Olga
authors.initials: O
authors.lastname: Pletnikova
authors.forename: Juan C
authors.initials: JC
authors.lastname: Troncoso
authors.forename: Valina L
authors.initials: VL
authors.lastname: Dawson
authors.forename: Ted M
authors.initials: TM
authors.lastname: Dawson
authors.forename: Han Seok
authors.initials: HS
authors.lastname: Ko
mesh_terms: D000368:Aged; D000818:Animals; D001921:Brain / Q000378:metabolism*; D004195:Disease Models, Animal; D005260:Female; D017353:Gene Deletion; D057809:HEK293 Cells; D006801:Humans; D016631:Lewy Bodies / Q000378:metabolism; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D009154:Mutation; D016501:Neurites / Q000378:metabolism; D019636:Neurodegenerative Diseases / Q000378:metabolism*; D000066829:Neuroprotection; D010300:Parkinson Disease / Q000235:genetics; D010766:Phosphorylation; D019000:Phosphotyrosine / Q000378:metabolism; D016315:Proto-Oncogene Proteins c-abl / Q000235:genetics / Q000378:metabolism*; D051844:alpha-Synuclein / Q000235:genetics / Q000378:metabolism*
chemical_list: D051844:alpha-Synuclein; D019000:Phosphotyrosine; D016315:Proto-Oncogene Proteins c-abl