Progressive degeneration of human neural stem cells caused by pathogenic LRRK2

Aging and its physiological manifestations have been correlated with adult stem cell exhaustion and a failure to maintain tissue homeostasis1-10. Since multiple morphological cellular defects are associated with aging-related disorders, we hypothesized that late onset disorders might be linked to adult stem cell abnormalities compromising cellular function over time. Our work shows that a dominant G2019S mutation in the human LRRK2 gene, which is associated with central nervous system disorders, including Parkinson's disease, the second most prevalent neurodegenerative disease in the aging population, causes alterations in neural stem cell homeostasis in aging-related cellular contexts. They include disruption of the nuclear architecture, deficiencies in clonal expansion and alterations in neural differentiation assays as well as an increased susceptibility to proteasomal stress. These phenotypic changes are dependent on differential kinase activity manifested during cellular passaging. Our studies might open new venues for studying the influence of aging in neural stem cell dependent processes, such as cognitive impairments, in the degenerating diseased brain. Overall design: Genome-wide localization of Histon K4 trimethylation in human iPSC and iPSC-derived neural stem cell using ChIP-seq

衰老及其生理学表型与成体干细胞耗竭及组织稳态维持障碍显著相关1-10。鉴于多种形态学细胞缺陷与衰老相关疾病存在关联，我们提出假说：迟发性疾病可能与随时间推移损害细胞功能的成体干细胞异常相关。本研究证实，人类LRRK2基因上的显性G2019S突变——该突变与包括帕金森病在内的中枢神经系统疾病相关，而帕金森病是衰老人群中第二大高发的神经退行性疾病——会在衰老相关细胞环境中引发神经干细胞稳态异常。这些异常包括核架构破坏、克隆扩增能力缺陷、神经分化实验中的表型改变，以及细胞对蛋白酶体应激的易感性升高。上述表型变化依赖于细胞传代过程中所展现的差异激酶活性。本研究或可为探究衰老对退行性病变大脑中神经干细胞依赖的生物学过程（如认知障碍）的影响开辟新方向。整体实验设计：采用染色质免疫沉淀测序（ChIP-seq）技术，检测人类诱导多能干细胞（induced pluripotent stem cell, iPSC）及其分化获得的神经干细胞中组蛋白H3K4三甲基化的全基因组定位情况。