C9orf72 六核苷酸重複序列與hnRNP H1之間的交互作用
Other Title
Exploring the structure of C9orf72 hexanucleotide repeat expansion and its interactions with hnRNP H1
Journal
2025臺大學士論文獎
Date Issued
2025
Author(s)
Han-Yu Chang
Advisor
Abstract
The human C9orf72 hexanucleotide (GGGGCC) repeat expansion (HRE) is a common genetic cause of both amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). Past studies indicated RNA foci formed by C9orf72 HRE are strongly related to the diseases in different aspects. One of the known features of RNA foci was to sequester RNA-binding proteins (RBPs). Several RBPs were found to colocalize with the RNA foci found in neuron cells of c9ALS patients. Among them, hnRNP H1, a splicing factor with a preference for binding G-rich sequences, has been found to be predominant in ALS/FTD patients with C9orf72 HRE. Although the common cause of these diseases has been identified, the underlying pathogenic mechanisms are yet unclear. Not to mention the function of hnRNP H1 in ALS/FTD.
To peek into the structural features of r(G4C2)n and the role of hnRNP H1 in the diseases, optical tweezers were applied in this research to monitor the real-time conformational change of RNA and its interaction with hnRNP H1. Through the unique single-molecule manipulations and measurements, we could determine the dynamic conformations of the RNA. Furthermore, hnRNP H1-N1, a truncation mutant of hnRNP H1, was added to determine its effect on the conformation of GGGGCC tandem repeats. Our results indicate that the short repeat of GGGGCC RNA was unable to form intramolecular G quadruplexes but still exhibited structural variations.
In the presence of the protein, the GGGGCC RNA could be remodeled to new conformations, suggesting that hnRNP H1-N1’s binding has a structural specificity. Moreover, the protein-targeted structure tends to be destabilized by hnRNP H1-N1. The emergence of the protein-induced structure provides a great insight into the function of hnRNP H1. We will tackle these issues in future experiments.
Subjects
C9orf72 HRE
amyotrophic lateral sclerosis
frontotemporal dementia
RNA foci, hnRNP H1
optical tweezers
Publisher
國立臺灣大學生命科學系
Description
獎項：校長獎；指導教授：温進德
Type
thesis
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