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

ABSTRACT: Aggregation of ?-synuclein contributes to the formation of Lewy bodies and neurites, the pathologic hallmarks of Parkinson disease (PD) and ?-synucleinopathies. Although a number of human mutations have been identified in familial PD, the mechanisms that promote ?-synuclein accumulation and toxicity are poorly understood. Here, we report that hyperactivity of the nonreceptor tyrosine kinase c-Abl critically regulates ?-synuclein-induced neuropathology. In mice expressing a human ?-synucleinopathy-associated mutation (hA53T?-syn mice), deletion of the gene encoding c-Abl reduced ?-synuclein aggregation, neuropathology, and neurobehavioral deficits. Conversely, overexpression of constitutively active c-Abl in hA53T?-syn mice accelerated ?-synuclein aggregation, neuropathology, and neurobehavioral deficits. Moreover, c-Abl activation led to an age-dependent increase in phosphotyrosine 39 ?-synuclein. In human postmortem samples, there was an accumulation of phosphotyrosine 39 ?-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 ?-synuclein at tyrosine 39 enhances ?-synuclein aggregation. Taken together, this work establishes a critical role for c-Abl in ?-synuclein-induced neurodegeneration and demonstrates that selective inhibition of c-Abl may be neuroprotective. This study further indicates that phosphotyrosine 39 ?-synuclein is a potential disease indicator for PD and related ?-synucleinopathies.

SUBMITTER: Brahmachari S 

PROVIDER: S-EPMC4966315 | biostudies-literature | 2016 Aug

REPOSITORIES: biostudies-literature