Activation of tyrosine kinase c-Abl contributes to α-synuclein–induced neurodegeneration
Saurav Brahmachari, … , Ted M. Dawson, Han Seok Ko
Saurav Brahmachari, … , Ted M. Dawson, Han Seok Ko
Published June 27, 2016
Citation Information: J Clin Invest. 2016;126(8):2970-2988. https://doi.org/10.1172/JCI85456.
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Research Article Neuroscience

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

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

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Figure 8

Phosphotyrosine 39 α-synuclein level is elevated in PD patients and accumulates in Lewy bodies.

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Phosphotyrosine 39 α-synuclein level is elevated in PD patients and accu...
(A, C, and E) Representative immunoblots of c-Abl, pY245 c-Abl, pY39 α-syn, pS129 α-syn, α-syn, and β-actin in the total lysates from substantia nigra, striatum, and cortex regions from PD patient brains and age-matched controls. (B) Quantification of c-Abl protein level normalized to β-actin, pY245 c-Abl protein level normalized to c-Abl, and pY39 α-syn and pS129 α-syn protein levels normalized to α-syn in the substantia nigra (control n = 5, PD n = 8). (D and F) Quantification of pY245 c-Abl protein level normalized to c-Abl and pY39 α-syn and pS129 α-syn protein levels normalized to α-syn in the striatum (control n = 5, PD n = 7) (D) and cortex (control n = 7, PD n = 6). Data are from 3 independent experiments. Statistical significance was determined by 2-tailed unpaired Student’s t test. Quantified data are expressed as the mean ± SEM. *P < 0.05, **P < 0.01. (G and I) Representative pY39 α-syn and pS129 α-syn IHC in the substantia nigra from PD patient brains and age-matched controls (n = 2). Scale bars: 250 μm. (H and J) High-magnification images of G and I. Scale bars: 25 μm.