作者
Andrew B Caldwell, Qing Liu, Gary P Schroth, Douglas R Galasko, Shauna H Yuan, Steven L Wagner, Shankar Subramaniam
发表日期
2019/1/29
期刊
bioRxiv
页码范围
531202
出版商
Cold Spring Harbor Laboratory
简介
Early-Onset Familial Alzheimer’s Disease (EOFAD) is a dominantly inherited neurodegenerative disorder elicited by over 300 mutations in the PSEN1, PSEN2, and APP genes. Hallmark pathological changes and symptoms observed, namely the accumulation of misfolded Amyloid-β (Aβ) in plaques and Tau aggregates in neurofibrillary tangles associated with memory loss and cognitive decline, are understood to be temporally accelerated manifestations of the more common sporadic Late-Onset Alzheimer’s Disease. The complete penetrance of EOFAD-causing mutations has allowed for experimental models which have proven integral to the overall understanding of AD. However, the failure of pathology-targeting therapeutic development suggests that the formation of plaques and tangles may be symptomatic and not describe the etiology of the disease,. In this work, we used an integrative, multi-omics approach and systems-level analysis in hiPSC-derived neurons to generate a mechanistic disease model for EOFAD. Using patient-specific cells from donors harboring mutations in PSEN1 differentiated into neurons, we characterized the disease-related gene expression and chromatin accessibility changes by RNA-Seq, ATAC-Seq, and histone methylation ChIP-Seq. Here, we show that the defining disease-causing mechanism of EOFAD is dedifferentiation, causing neurons to traverse the lineage-defining chromatin landscape along an alternative axis to a mixed-lineage cell state with gene signature profiles indicative of less-defined ectoderm as well as non-ectoderm lineages via REST-mediated repression of neuronal lineage specification …
学术搜索中的文章
AB Caldwell, Q Liu, GP Schroth, DR Galasko, SH Yuan… - bioRxiv, 2019