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Molecular and Computational Studies of TDP-43 and FUS Proteinopathies
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| 자료유형 | 학위논문 |
|---|---|
| 서명/저자사항 | Molecular and Computational Studies of TDP-43 and FUS Proteinopathies. |
| 개인저자 | McGee, Warren. |
| 단체저자명 | Northwestern University. Interdepartmental Neuroscience Program (NUIN). |
| 발행사항 | [S.l.]: Northwestern University., 2019. |
| 발행사항 | Ann Arbor: ProQuest Dissertations & Theses, 2019. |
| 형태사항 | 172 p. |
| 기본자료 저록 | Dissertations Abstracts International 81-02B. Dissertation Abstract International |
| ISBN | 9781085601900 |
| 학위논문주기 | Thesis (Ph.D.)--Northwestern University, 2019. |
| 일반주기 |
Source: Dissertations Abstracts International, Volume: 81-02, Section: B.
Includes supplementary digital materials. Advisor: Wu, Jane Y. |
| 이용제한사항 | This item must not be sold to any third party vendors.This item must not be sold to any third party vendors. |
| 요약 | Frontotemporal Dementia (FTD) and Amyotrophic Lateral Sclerosis (ALS) are two devastating neurodegenerative diseases that affect 100,000s of people globally. They have a severe adverse impact on society, yet there are currently no early diagnostic tools or disease-modifying therapies available. Despite their clinical heterogeneity, evidence points to these diseases being on a spectrum, with shared molecular characteristics.Two proteins known to be associated with the disease spectrum are TDP-43 and FUS, both multifunctional DNA- and RNA-binding proteins. These two proteins share common structural features, have a core of common target genes, and have similar functions throughout the lifecycle of RNA, regulating transcription, splicing, localization, translation and stability. However, they also have distinct characteristics and differences as well. For both proteins, the current paradigm says that a combination of factors leads to nuclear clearance and aggregation into cytosolic inclusion bodies. An unresolved debate in the field is whether the disease occurs through loss-of-function or gain-of-toxicity mechanisms.This work was motivated to better understand the endogenous roles these proteins play in regulating the nervous system. In particular, much recent work has provided evidence that both proteins are involved with miRNA biogenesis and mitochondrial function, both of which have been implicated in the pathogenesis of the ALS-FTD spectrum. Because of the complexity of the number of potential RNA targets, a genome-wide approach is essential for understanding the roles of these proteins. Thus, we sought to explore both of these functions systematically using a combination of molecular biology and bioinformatics.We first systematically examined which miRNAs are regulated by TDP-43 and FUS in neuronal model systems. In this work, we designed a novel pipeline to both predict which miRNA-mRNA interactions are occurring in our model system, but also which pathways might be dysregulated. We identified FUS-regulated miRNAs that had established and predicted roles in synaptic regulation. Intriguingly, we identified several cancer-associated miRNAs regulated by TDP-43, with several TDP-43-regulated miRNAs predicted to have novel roles in lung cancer pathogenesis and prognosis. In particular, our pipeline identified one miRNA, miR-423-3p, with a predicted role in regulating cell migration. Follow-up experiments validated this prediction, demonstrating the power of this network approach.We next sought to determine which mitochondrial-associated genes may be regulated by FUS. In the course of initial work in this area, we realized that RNA-Sequencing data is compositional rather than count data. This means that it carries only relative information, not information about absolute copy number changes. Standard normalization methods can lead to distorted results if there is significantly more RNA in one condition versus another. We thus designed a new normalization approach, called compositional normalization (implemented in an extension of the popular sleuth tool, called sleuth-ALR), to deal with this problem, and we also designed a new simulation protocol, absSimSeq, to benchmark performance in a more accurate way. Compositional normalization performed similarly to standard normalization when analyzing data that did not have large number of changes |
| 일반주제명 | Neurosciences. Molecular biology. Bioinformatics. |
| 언어 | 영어 |
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