Activation of tyrosine kinase c-Abl contributes to α-synuclein-induced neurodegeneration

Saurav Brahmachari, Preston Ge, Su Hyun Lee, Donghoon Kim, Senthilkumar Karuppagounder, Manoj Kumar, Xiaobo Mao, Joo Ho Shin, Yunjong Lee, Olga Pletnikova, Juan C Troncoso, Valina Dawson, Ted M Dawson, Hanseok Seok Ko

Research output: Contribution to journalArticle

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.

Original languageEnglish (US)
Pages (from-to)2970-2988
Number of pages19
JournalJournal of Clinical Investigation
Volume126
Issue number8
DOIs
StatePublished - Aug 1 2016

ASJC Scopus subject areas

  • Medicine(all)

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