背景:在与PD风险增加相关的基因突变和变异中,富含亮氨酸的重复序列激酶2基因(LRRK2)的突变是最常见的与早发性和晚发性PD相关的突变.特发性PD(iPD)和LRRK2-PD的临床和神经病理学特征相似,这些相似性表明这两种情况之间的病理机制是共有的。LRRK2突变决定了功能的获得,并在整个身体组织中产生更高水平的lrrk2,包括大脑。另一方面,最近的动物研究支持使用低剂量辐射(LDR)来改变阿尔茨海默病(AD)等疾病的病理机制。
方法:我们评估了正常猪的单一全身LDR(sLDR)暴露是否可以改变以下PD相关分子的表达水平:α-突触核蛋白(α-syn),磷酸化-α-突触核蛋白(pα-syn),Parkin,酪氨酸羟化酶(th),lrrk2,磷酸化-lrrk2(pS935-lrrk2),和一些LRRK2底物(Rab8a,Rab12)跨不同的大脑区域。这些蛋白质是在额叶皮层中测量的,海马体,纹状体,丘脑/下丘脑,9辐射小脑(RAD)与从1.79Gy的sLDR暴露28天后,6头假(SH)猪。
结果:Western印迹分析显示,RAD纹状体中的lrrk2水平与SH猪(p<0.05),其余大脑区域没有差异。在任何检查的大脑区域中,RAD和SH猪之间的其他蛋白质水平均无差异。没有lrrk2和p-lrrk2(S935)水平在RAD与肺的差异SH猪。
结论:这些发现显示了LDR引起的特定纹状体lrrk2降低作用,并支持LDR可能用于干扰PD的病理机制。
BACKGROUND: Among gene mutations and variants linked to an increased risk of PD, mutations of leucine-rich repeat kinase 2 gene (LRRK2) are among the most frequently associated with early- and late-onset PD. Clinical and neuropathological characteristics of idiopathic-PD (iPD) and LRRK2-PD are similar, and these similarities suggest that the pathomechanisms between these two conditions are shared. LRRK2 mutations determine a gain-of-function and yield higher levels of lrrk2 across body tissues, including brain. On another side, recent animal studies supported the potential use of low dose radiation (LDR) to modify the pathomechanisms of diseases such as Alzheimer\'s disease (AD).
METHODS: We assessed if a single total-body LDR (sLDR) exposure in normal swine could alter expression levels of the following PD-associated molecules: alpha-synuclein (α-syn), phosphorylated-α-synuclein (pα-syn), parkin, tyrosine hydroxylase (th), lrrk2, phosphorylated-lrrk2 (pS935-lrrk2), and some LRRK2 substrates (Rab8a, Rab12) across different brain regions. These proteins were measured in frontal cortex, hippocampus, striatum, thalamus/hypothalamus, and cerebellum of 9 radiated (RAD) vs. 6 sham (SH) swine after 28 days from a sLDR of 1.79Gy exposure.
RESULTS: Western Blot analyses showed lowered lrrk2 levels in the striatum of RAD vs. SH swine (p < 0.05), with no differences across the remaining brain regions. None of the other protein levels differed between RAD and SH swine in any examined brain regions. No lrrk2 and p-lrrk2 (S935) levels differed in the lungs of RAD vs. SH swine.
CONCLUSIONS: These findings show a specific striatal lrrk2 lowering effect due to LDR and support the potential use of LDR to interfere with the pathomechanisms of PD.