Activation of tyrosine kinase c-Abl contributes to α-synuclein-induced neurodegeneration
Activation of tyrosine kinase c-Abl contributes to α-synuclein-induced neurodegeneration
复制标题
DOI：
10.1172/jci85456
复制
发表时间：
2016-08-01
影响因子：
15.9
通讯作者：
Ko, Han Seok
中科院分区：
文献类型：
--
作者：
Brahmachari, Saurav;Ge, Preston;Ko, Han Seok
α-突触核蛋白的聚集有助于路易体和神经突的形成，路易体和神经突是帕金森病（PD）和α-突触核蛋白病的病理标志。虽然在家族性PD中已经鉴定出许多人类突变，但对促进α-突触核蛋白积累和毒性的机制知之甚少。在这里，我们报告说，过度活跃的非受体酪氨酸激酶c-Abl严重调节α-突触核蛋白诱导的神经病理学。在表达人α-突触核蛋白病相关突变的小鼠（hA 53 T α-syn小鼠）中，编码c-Abl的基因的缺失减少了α-突触核蛋白聚集、神经病理学和神经行为缺陷。相反，hA 53 T alpha-syn小鼠中组成型活性c-Abl的过表达加速了α-突触核蛋白聚集、神经病理学和神经行为缺陷。此外，c-Abl激活导致磷酸酪氨酸39 α-突触核蛋白的年龄依赖性增加。在人类尸检样本中，与年龄匹配的对照组相比，PD患者的脑组织和路易体中存在磷酸酪氨酸39 α-突触核蛋白的积累。此外，体外研究表明，α-突触核蛋白在酪氨酸39处的c-Abl磷酸化增强α-突触核蛋白聚集。总之，这项工作确立了c-Abl在α-突触核蛋白诱导的神经变性中的关键作用，并证明了c-Abl的选择性抑制可能具有神经保护作用。这项研究进一步表明，磷酸酪氨酸39 α-突触核蛋白是PD和相关α-突触核蛋白病的潜在疾病指标。
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 (hA53T alpha-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 hA53T alpha-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.