Distinct mechanisms of axonal globule formation in mice expressing human wild type α-synuclein or dementia with Lewy bodies-linked P123H β-synuclein.
Distinct mechanisms of axonal globule formation in mice expressing human wild type α-synuclein or dementia with Lewy bodies-linked P123H β-synuclein.
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DOI：
10.1186/1756-6606-5-34
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发表时间：
2012-09-26
期刊：
影响因子：
3.6
通讯作者：
Hashimoto M
中科院分区：
文献类型：
--
作者：
Sekigawa A;Fujita M;Sekiyama K;Takamatsu Y;Hatano T;Rockenstein E;La Spada AR;Masliah E;Hashimoto M
轴突病变在神经退行性疾病的早期发病机制中起关键作用，包括帕金森病(PD)和路易体痴呆(DLB)。轴突肿胀是轴索病的一个明显特征，我们最近的研究表明，表达DLb连接的P123Hβ-突触核蛋白的转基因(TG)小鼠(P123HβS)具有P123HβS免疫反应阳性的轴突肿胀(P123HβS球状)的特征。因此，本研究的目的是观察α-突触核蛋白(αS)免疫反应阳性的轴突肿胀(αS球)在表达人野生型αS的TG小鼠的脑中，并将它们与P123HβS TG小鼠的球进行比较。在αS TG小鼠中，αS小球在丘脑和基底节等不同脑区以年龄依赖的方式形成。这些小球由自噬体样膜结构组成，与P123HβS TG小鼠的P123HβS小球相似。在αS小球中，观察到线粒体频繁聚集和变形。这些变化与氧化应激有关，基于硝化αS和4-羟基-2-壬烯醛(4-HNE)的染色。与P123HβS颗粒中线粒体的缺失相一致，硝化αS和4-HNE在这些颗粒中的染色弱于αS颗粒。家族性帕金森病的Park8富含亮氨酸重复蛋白2(LRRK2)仅在αS球体中检测到，提示该分子在这些球体中起着特殊的作用。αS小球和P123HβS小球的溶酶体病理相似，而氧化应激与αS小球有关，与P123HβS小球的关系较小。其他病理改变，如线粒体改变和LRRK2积聚，仅在αS球粒中检测到。总的来说，αS和P123HβS都是通过相似但不同的致病机制形成的。我们的发现表明，突触核蛋白家族成员可能参与了不同的轴突病理。
Axonopathy is critical in the early pathogenesis of neurodegenerative diseases, including Parkinson’s disease (PD) and dementia with Lewy bodies (DLB). Axonal swellings such as globules and spheroids are a distinct feature of axonopathy and our recent study showed that transgenic (tg) mice expressing DLB-linked P123H β-synuclein (P123H βS) were characterized by P123H βS-immunoreactive axonal swellings (P123H βS-globules). Therefore, the objectives of this study were to evaluate α-synuclein (αS)-immunoreactive axonal swellings (αS-globules) in the brains of tg mice expressing human wild-type αS and to compare them with the globules in P123H βS tg mice. In αS tg mice, αS-globules were formed in an age-dependent manner in various brain regions, including the thalamus and basal ganglia. These globules were composed of autophagosome-like membranous structures and were reminiscent of P123H βS-globules in P123H βS tg mice. In the αS-globules, frequent clustering and deformation of mitochondria were observed. These changes were associated with oxidative stress, based on staining of nitrated αS and 4-hydroxy-2-nonenal (4-HNE). In accord with the absence of mitochondria in the P123H βS-globules, staining of nitrated αS and 4-HNE in these globules was weaker than that for αS-globules. Leucine-rich repeat kinase 2 (LRRK2), the PARK8 of familial PD, was detected exclusively in αS-globules, suggesting a specific role of this molecule in these globules. Lysosomal pathology was similarly observed for both αS- and P123H βS-globules, while oxidative stress was associated with the αS-globules, and to a lesser extent with the P123H βS-globules. Other pathologies, such as mitochondrial alteration and LRRK2 accumulation, were exclusively detected for αS-globules. Collectively, both αS- and P123H βS-globules were formed through similar but distinct pathogenic mechanisms. Our findings suggest that synuclein family members might contribute to diverse axonal pathologies.
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影响因子：
16.2
作者：
Giasson, BI;Duda, JE;Lee, VMY
通讯作者：
Lee, VMY
影响因子：
25
作者：
Li, Yanping;Liu, Wencheng;Oo, Tinmarla F.;Wang, Lei;Tang, Yi;Jackson-Lewis, Vernice;Zhou, Chun;Geghman, Kindiya;Bogdanov, Mikhail;Przedborski, Serge;Beal, M. Flint;Burke, Robert E.;Li, Chenjian
通讯作者：
Li, Chenjian
影响因子：
6
作者：
Galvin, JE;Giasson, B;Trojanowski, JQ
通讯作者：
Trojanowski, JQ
DOI：
10.1073/pnas.132197599
发表时间：
2002-06-25
影响因子：
11.1
作者：
Lee, MK;Stirling, W;Price, DL
通讯作者：
Price, DL
影响因子：
14.8
作者：
Bosco, DA;Fowler, DM;Kelly, JW
通讯作者：
Kelly, JW