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Transcriptional Inhibition of (GGGGCC) c9orf72 Hexanucleotide Repeat Expansion in Frontotemporal Dementia and Amyotrophic Lateral Sclerosis.

紀錄類型:	書目-電子資源 : Monograph/item
正題名/作者:	Transcriptional Inhibition of (GGGGCC) c9orf72 Hexanucleotide Repeat Expansion in Frontotemporal Dementia and Amyotrophic Lateral Sclerosis./
作者:	Kim, Yujin E.
面頁冊數:	1 online resource (97 pages)
附註:	Source: Dissertations Abstracts International, Volume: 80-10, Section: B.
Contained By:	Dissertations Abstracts International80-10B.
標題:	Neurosciences. -
電子資源:	http://pqdd.sinica.edu.tw/twdaoapp/servlet/advanced?query=13857411click for full text (PQDT)
ISBN:	9781392057384

Transcriptional Inhibition of (GGGGCC) c9orf72 Hexanucleotide Repeat Expansion in Frontotemporal Dementia and Amyotrophic Lateral Sclerosis.
Kim, Yujin E.

Transcriptional Inhibition of (GGGGCC) c9orf72 Hexanucleotide Repeat Expansion in Frontotemporal Dementia and Amyotrophic Lateral Sclerosis. - 1 online resource (97 pages)

Source: Dissertations Abstracts International, Volume: 80-10, Section: B.

Thesis (Ph.D.)--College of Medicine - Mayo Clinic, 2019.

Includes bibliographical references

Microsatellite repeat mutations are long expansions of repetitive DNA in the genome. Two Dozen of devastating neurological disorders are associated with the DNA repeat expansions including Frontotemporal dementia and amyotrophic lateral sclerosis (FTD/ALS). The pathogenic mechanisms include RNA toxicity, RNA binding protein sequestration and/or repeat peptide toxicity contributing to the diseases. To prevent these consequences at the fundamental level, I focus on targeting transcription of the repeat expansions via two mechanisms; one is to target the specific anti-parallel G-Quadruplex(G-Q) structure of the (GGGGCC) repeat expansion and the other is targeting the protein-protein interaction (PPI) of the transcription elongation factor in charge of elongation of the repeat mutations. As a component of RNA Polymerase II transcription machinery, Spt4 (Supt4h1) forms a dimer to Spt5 to assist the expression of longer repeat expansions. We utilized the (GGGGCC)4 G-Q structure to do docking modeling of 58,000 CNS compounds to find the best binders and tested on overexpression cell model and induced Neurons to assess their modulation activities on c9. As the only binding partner of Spt4 is Spt5 in the complex, we aim to target PPI at the Spt5 interaction domain of Spt4 to expel Spt4 from the elongation complex to get therapeutic effect against microsatellite repeat mutations. Computational structural prediction modeling was done using co-crystal structures of Spt4/partial Spt5 (PDB: 3H7H) in multiple steps. Here, we confirm that I61-M64 of Spt4 and K213-A217 of Spt5 are critical regions to form a heterodimer. 10 peptides were designed based on these regions. Peptide1 which mimics Spt5 binding motif of Spt4 significantly inhibits the heterodimer formation, as evidenced by 80% signal reduction in peptide incubation assay and a 40% decrease upon treatment in cell-based luminescence assay. Induced Neurons treated with 7730200, the G-Q binder has a significant reduction in RNA foci and poly-(GP) proteins.

Electronic reproduction.
Ann Arbor, Mich. :
ProQuest,
2023

Mode of access: World Wide Web

ISBN: 9781392057384Subjects--Topical Terms:

588700
Neurosciences.
Subjects--Index Terms:

BioinformaticsIndex Terms--Genre/Form:

542853
Electronic books.

Transcriptional Inhibition of (GGGGCC) c9orf72 Hexanucleotide Repeat Expansion in Frontotemporal Dementia and Amyotrophic Lateral Sclerosis.
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