Involvement of the cerebral cortex in Parkinson disease linked with G2019S LRRK2 mutation without cognitive impairment
Involvement of the cerebral cortex in Parkinson disease linked with G2019S LRRK2 mutation without cognitive impairment
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DOI：
10.1007/s00401-010-0669-y
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发表时间：
2010-08-01
影响因子：
12.7
通讯作者：
Ferrer, Isidre
中科院分区：
文献类型：
--
作者：
Gomez, Anna;Ferrer, Isidre
先前的研究表明，在没有认知障碍的散发性帕金森病(PD)患者中，突触核蛋白改变、氧化应激损伤增加和氧化应激反应增加。然而，目前还没有关于家族性帕金森病患者大脑皮层可能发生分子变化的信息。本研究显示与G2019S LRRK2突变相关的长效帕金森病患者大脑皮层(第8区)α-突触核蛋白溶解和聚集异常，并聚集硝化的α-突触核蛋白，其中1例大脑皮层有少量路易小体(LBS)，另外两例大脑皮层无LBS。与平行处理的三个对照组相比，三个LRRK2病例的额叶皮质氧化应激标志物丙二醛赖氨酸(MDAL)的表达增加，氧化应激反应、AGE受体(RAGE)和超氧化物歧化酶2(Superoxdismuase 2)的增加。双向凝胶电泳法、Western blotting、凝胶内消化和质谱仪显示，胶质纤维酸性蛋白是MDAL加合物的靶标。微管蛋白β4和烯醇化酶2也被确定为氧化损伤的目标。这些结果表明，与G2019S LRRK2突变相关的帕金森病患者额叶皮质α-突触核蛋白生化异常，氧化应激损伤和氧化应激反应增加，与皮质LBS的存在和无明显认知障碍无关。这些发现表明，G2019S LRRK2连锁的家族性帕金森病患者的大脑皮层受影响的方式与无认知损害的散发性帕金森病患者相似。
Previous studies have shown altered synuclein, increased oxidative stress damage and increased oxidative stress responses in patients with sporadic Parkinson's disease (PD) without cognitive impairment. Yet no information exists about possible molecular alterations in the cerebral cortex in familial PD. The present study shows abnormal alpha-synuclein solubility and aggregation, and aggregated nitrated alpha-synuclein, in the cerebral cortex (area 8) in cases with long-lasting PD linked with the G2019S LRRK2 mutation, one of them with a few Lewy bodies (LBs) and the other two without LBs in the cerebral cortex. Increased expression of the oxidative stress marker malondialdehyde-lysine (MDAL), together with increased oxidative stress responses, AGE receptors (RAGE) and superoxide dismutase 2, occurred in the frontal cortex in the three LRRK2 cases compared with three controls processed in parallel. Bi-dimensional gel electrophoresis, western blotting, in-gel digestion and mass spectrometry disclosed glial fibrillary acidic protein as a target of MDAL adducts. Tubulin beta 4 and enolase 2 were also identified as targets of oxidative damage. These results demonstrate biochemical abnormalities of alpha-synuclein, and increased oxidative stress damage and oxidative stress responses in the frontal cortex in PD linked with G2019S LRRK2 mutation not related with the presence of cortical LBs and in the absence of apparent cognitive deficits. These findings show that the cerebral cortex in familial PD linked with G2019S LRRK2 is affected in a similar way than that seen in sporadic PD without cognitive impairment.