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- Title
Activation of tyrosine kinase c-Abl contributes to α-synuclein-induced neurodegeneration.
- Authors
Brahmachari, Saurav; Ge, Preston; Su Hyun Lee; Donghoon Kim; Karuppagounder, Senthilkumar S.; Kumar, Manoj; Xiaobo Mao; Joo Ho Shin; Yunjong Lee; Pletnikova, Olga; Troncoso, Juan C.; Dawson, Valina L.; Dawson, Ted M.; Han Seok Ko; Lee, Su Hyun; Kim, Donghoon; Mao, Xiaobo; Shin, Joo Ho; Lee, Yunjong; Ko, Han Seok
- 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.
- Subjects
LEWY body dementia; NEURONS; PARKINSON'S disease; PROTEIN-tyrosine kinases; PHOSPHOTYROSINE; BRAIN metabolism; TYROSINE metabolism; ANIMAL experimentation; BIOLOGICAL models; EPITHELIAL cells; MICE; GENETIC mutation; NERVE tissue proteins; NEURODEGENERATION; PHOSPHORYLATION
- Publication
Journal of Clinical Investigation, 2016, Vol 126, Issue 8, p2970
- ISSN
0021-9738
- Publication type
journal article
- DOI
10.1172/JCI85456