| First Author | Brahmachari S | Year | 2016 |
| Journal | J Clin Invest | Volume | 126 |
| Issue | 8 | Pages | 2970-88 |
| PubMed ID | 27348587 | Mgi Jnum | J:232550 |
| Mgi Id | MGI:5779538 | Doi | 10.1172/JCI85456 |
| Citation | Brahmachari S, et al. (2016) Activation of tyrosine kinase c-Abl contributes to alpha-synuclein-induced neurodegeneration. J Clin Invest 126(8):2970-88 |
| abstractText | Aggregation of alpha-synuclein contributes to the formation of Lewy bodies and neurites, the pathologic hallmarks of Parkinson disease (PD) and alpha-synucleinopathies. Although a number of human mutations have been identified in familial PD, the mechanisms that promote alpha-synuclein accumulation and toxicity are poorly understood. Here, we report that hyperactivity of the nonreceptor tyrosine kinase c-Abl critically regulates alpha-synuclein-induced neuropathology. In mice expressing a human alpha-synucleinopathy-associated mutation (hA53Talpha-syn mice), deletion of the gene encoding c-Abl reduced alpha-synuclein aggregation, neuropathology, and neurobehavioral deficits. Conversely, overexpression of constitutively active c-Abl in hA53Talpha-syn mice accelerated alpha-synuclein aggregation, neuropathology, and neurobehavioral deficits. Moreover, c-Abl activation led to an age-dependent increase in phosphotyrosine 39 alpha-synuclein. In human postmortem samples, there was an accumulation of phosphotyrosine 39 alpha-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 alpha-synuclein at tyrosine 39 enhances alpha-synuclein aggregation. Taken together, this work establishes a critical role for c-Abl in alpha-synuclein-induced neurodegeneration and demonstrates that selective inhibition of c-Abl may be neuroprotective. This study further indicates that phosphotyrosine 39 alpha-synuclein is a potential disease indicator for PD and related alpha-synucleinopathies. |
