Department of Medical Neurobiology (Physiology), IMRIC, The Hebrew University-Hadassah Medical School, Jerusalem, 91120 Israel.
Neurobiol Dis. 2012 Mar;45(3):1018-30. doi: 10.1016/j.nbd.2011.12.021. Epub 2011 Dec 16.
Both genetic and environmental factors trigger risks of and protection from Parkinson's disease, the second most common neurodegenerative syndrome, but possible inter-relationships between these risk and protection processes were not yet explored. By examining gene expression changes in the brains of mice under multiple treatments that increase or attenuate PD symptoms we detected underlying disease and protection-associated genes and pathways. In search for potential links between these different genes and pathways, we conducted meta-analysis on 131 brain region transcriptomes from mice over-expressing native or mutated α-synuclein (SNCA) with or without the protective HSP70 chaperone, or exposed to the dopaminergic neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), with or without the protective acetylcholinesterase (AChE-R) variant. All these models showed shared risk-inducible and protection-suppressible transcript modifications. Self-organized map (SOM) classification revealed risk- and protection-associated alterations in nuclear and mitochondrial metal ion-regulated transcripts, respectively; Gene Ontology based analysis validated these pathways. To complement this approach, and identify potential outcome damages, we further searched for shared functional enrichments in the lists of genes detected in young SNCA mutant or in old SNCA mutants and MPTP-exposed mice. This post-hoc functional analysis identified early-onset changes in Parkinsonian, immune and alternative splicing pathways which shifted into late-onset or exposure-associated NFkB-mediated neuro-inflammation. Our study suggests metal ions-mediated cross-talk between nuclear and mitochondrial pathways by both environmental and genetic risk and protective factors involved in Parkinson's disease, which eventually culminates in neuro-inflammation. Together, these findings offer new insights and novel targets for therapeutic interference with the gene-environment interactions underlying sporadic PD.
遗传和环境因素都可能引发帕金森病（第二大常见神经退行性疾病）的风险，但这些风险和保护过程之间的可能相互关系尚未得到探索。通过检查多种增加或减轻 PD 症状的治疗方法下小鼠大脑中的基因表达变化，我们检测到了潜在的疾病和保护相关基因和途径。为了寻找这些不同基因和途径之间的潜在联系，我们对 131 个大脑区域转录组进行了元分析，这些转录组来自过度表达天然或突变的α-突触核蛋白（SNCA）的小鼠，这些小鼠或不表达具有保护作用的热休克蛋白 70（HSP70）伴侣，或暴露于多巴胺能神经毒素 1-甲基-4-苯基-1,2,3,6-四氢吡啶（MPTP），这些小鼠或不表达具有保护作用的乙酰胆碱酯酶（AChE-R）变体。所有这些模型都显示出共享的风险诱导和保护抑制转录修饰。自组织映射（SOM）分类显示，风险相关和保护相关的改变分别发生在核和线粒体金属离子调节的转录物中；基于基因本体论的分析验证了这些途径。为了补充这种方法，并确定潜在的功能损伤，我们进一步在年轻的 SNCA 突变体或年老的 SNCA 突变体和 MPTP 暴露的小鼠中检测到的基因列表中寻找共享的功能富集。这种事后功能分析确定了帕金森病相关的早期变化，包括免疫和替代剪接途径，这些变化转变为晚期或与暴露相关的 NFkB 介导的神经炎症。我们的研究表明，环境和遗传风险和保护因素通过核和线粒体途径之间的金属离子介导的串扰，最终导致神经炎症。这些发现为治疗性干预与散发性帕金森病相关的基因-环境相互作用提供了新的见解和新的靶点。
