Distribution of Misfolded Prion Protein Seeding Activity Alone Does Not Predict Regions of Neurodegeneration.
Distribution of Misfolded Prion Protein Seeding Activity Alone Does Not Predict Regions of Neurodegeneration.
复制标题
DOI：
10.1371/journal.pbio.1002579
复制
发表时间：
2016-11
期刊：
影响因子：
9.8
通讯作者：
Manson JC
中科院分区：
文献类型：
--
作者：
Alibhai J;Blanco RA;Barria MA;Piccardo P;Caughey B;Perry VH;Freeman TC;Manson JC
蛋白质错误折叠在许多神经退行性疾病中是常见的，错误折叠的蛋白质充当正常折叠的蛋白质向异常构象的“朊病毒样”转化的种子。一个中心假设是，错误折叠的蛋白质的积累，扩散和分布仅限于中枢神经系统的特定神经元群体，从而预测神经变性的区域。我们使用高度敏感的检测系统检测朊病毒病小鼠模型中错误折叠的蛋白质种子来检验这一假设。错误折叠的朊病毒蛋白（PrP）种子被广泛观察到整个大脑，积累在所有的大脑区域检查，无论神经变性。重要的是，无论是暴露的时间还是错误折叠的蛋白质种子的量都不会呈现确定的神经变性区域。我们进一步证明了朊病毒感染的大脑中两种不同的小胶质细胞反应：所有区域的新型稳态反应和局限于神经变性部位的先天免疫反应。因此，错误折叠的朊病毒蛋白的单独积累并不能定义神经变性的靶向，相反，只有当错误折叠的朊病毒蛋白伴随特异性先天免疫应答时才会导致神经变性。错误折叠的朊病毒蛋白播种活性的分布本身并不能预测朊病毒疾病中的神经变性区域;相反，复杂的小胶质细胞反应似乎决定了选择性脆弱性，并提供了新的治疗策略。正常的大脑功能需要对蛋白质折叠进行严格的调节;当这一过程出错时，蛋白质会折叠成异常的构象，这对大脑性能产生严重影响，导致痴呆症等疾病。以前的研究表明，在大脑的限制部分发现了异常折叠的蛋白质，这些特定大脑区域的神经元细胞已被证明会发生变性。最近的技术进步增强了疾病期间异常折叠朊病毒蛋白（PrP）的检测;我们使用这些技术来测试异常折叠蛋白的分布是否确实局限于正在变性的大脑区域。令人惊讶的是，我们在整个大脑中观察到了异常折叠的蛋白质，这表明这些蛋白质可以在大脑中未显示退化的部分积累。因此，异常折叠蛋白质的分布本身不足以引起神经元变性。此外，我们发现小胶质细胞（大脑中的非神经元细胞类型之一）在朊病毒疾病期间以两种不同的方式改变它们的反应;一种反应与有弹性的大脑区域相关，第二种，炎症反应与易变性区域相关。因此，小胶质细胞的反应似乎是重要的，在确定疾病的结果。
Protein misfolding is common across many neurodegenerative diseases, with misfolded proteins acting as seeds for "prion-like" conversion of normally folded protein to abnormal conformations. A central hypothesis is that misfolded protein accumulation, spread, and distribution are restricted to specific neuronal populations of the central nervous system and thus predict regions of neurodegeneration. We examined this hypothesis using a highly sensitive assay system for detection of misfolded protein seeds in a murine model of prion disease. Misfolded prion protein (PrP) seeds were observed widespread throughout the brain, accumulating in all brain regions examined irrespective of neurodegeneration. Importantly, neither time of exposure nor amount of misfolded protein seeds present determined regions of neurodegeneration. We further demonstrate two distinct microglia responses in prion-infected brains: a novel homeostatic response in all regions and an innate immune response restricted to sites of neurodegeneration. Therefore, accumulation of misfolded prion protein alone does not define targeting of neurodegeneration, which instead results only when misfolded prion protein accompanies a specific innate immune response. The distribution of misfolded prion protein seeding activity alone does not predict regions of neurodegeneration in prion disease; rather, a complex microglial response appears to determine selective vulnerability and provides new strategies for therapy. Normal brain function requires tight regulation of protein folding; when this goes wrong, proteins can fold into abnormal conformations, which have severe impacts on brain performance, leading to conditions like dementia. Previous studies show that abnormally folded proteins are found in restricted parts of the brain, and neuronal cells in these specific brain regions have been shown to undergo degeneration. Recent technological advances have enhanced the detection of abnormally folded prion protein (PrP) during disease; we used these technologies to test whether distribution of abnormally folded proteins is indeed restricted to regions of the brain undergoing degeneration. Surprisingly, we observed abnormally folded proteins throughout the brain, demonstrating that these proteins can accumulate in parts of the brain that do not show degeneration. Thus, the distribution of abnormally folded protein, by itself, is not sufficient for neuronal degeneration. In addition, we found that microglia (one of the nonneuronal cell types in the brain) change their response during prion disease in two different ways; one response is associated with resilient brain regions, and the second, an inflammatory response is associated with regions susceptible to degeneration. Thus, the microglial response appears to be important in determining the outcome of disease.
登录
查看更多内容
DOI：
10.1186/1745-7580-4-5
发表时间：
2008-04-29
期刊：
Immunome research
影响因子：
--
作者：
Lattin JE;Schroder K;Su AI;Walker JR;Zhang J;Wiltshire T;Saijo K;Glass CK;Hume DA;Kellie S;Sweet MJ
通讯作者：
Sweet MJ
影响因子：
6.1
作者：
Boche, Delphine;Cunningham, Colm;Perry, V. Hugh
通讯作者：
Perry, V. Hugh
影响因子：
3.7
作者：
Campeau JL;Wu G;Bell JR;Rasmussen J;Sim VL
通讯作者：
Sim VL
影响因子：
5
作者：
Jeffrey, M;Halliday, WG;Fraser, JR
通讯作者：
Fraser, JR
DOI：
10.1016/j.nurt.2010.05.014
发表时间：
2010-10
期刊：
Neurotherapeutics : the journal of the American Society for Experimental NeuroTherapeutics
影响因子：
--
作者：
Lull ME;Block ML
通讯作者：
Block ML