4.5 Article

Aggregation and the Intrinsic Structural Disorder of Dipeptide Repeat Peptides of C9orf72-Related Amyotrophic Lateral Sclerosis and Frontotemporal Dementia Characterized by NMR

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JOURNAL OF PHYSICAL CHEMISTRY B
卷 125, 期 45, 页码 12446-12456

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AMER CHEMICAL SOC
DOI: 10.1021/acs.jpcb.1c08149

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资金

  1. National Institutes of Health (NIH) [AG048934, 9R01NS096785-06]
  2. University of Michigan (UM) Protein Folding Disease Initiative
  3. UM M-cubed
  4. NIH [AG048934]

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DPRs play crucial roles in ALS and FTD, with (GA)6 and (GR)6 forming neurotoxic aggregates while (GP)6 does not aggregate. Feasibility of high-resolution monitoring of peptide aggregation was explored using NMR experiments, demonstrating the ability to detect minor conformational changes and aggregation kinetics.
Dipeptide repeats (DPRs) are known to play important roles in C9ORF72-related amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). Studies on DPRs have reported on the kinetics of aggregation, toxicity, and low-resolution morphology of the aggregates of these peptides. While the dipeptide hexa-repeats of Gly-Pro [(GP)(6)] have been shown to be nonaggregating, Gly-Ala [(GA)(6)] and Gly-Arg [(GR)(6)] exhibited the formation of neurotoxic aggregates. However, structural studies of these DPRs have been elusive. In this study, we explored the feasibility of a high-resolution monitoring of a real-time aggregation of these peptides in a solution by using NMR experiments. Although (GP)(6) is disordered and nonaggregating, the existence of cis and trans conformations was observed from NMR spectra. It was remarkable that the (GR)(6) exhibited the formation of multiple conformations, whereas the hydrophobic and low-soluble (GA)(6) aggregated fast in a temperature-dependent manner. These results demonstrate the feasibility of monitoring the minor conformational changes from highly disordered peptides, aggregation kinetics, and the formation of small molecular weight aggregates by solution NMR experiments. The ability to detect cis and trans local isomerizations in (GP)(6) is noteworthy and could be valuable to study intrinsically disordered proteins/peptides by NMR. The early detection of minor conformational changes could be valuable in better understanding the mechanistic insights into the formation of toxic intermediates and the development of approaches to inhibit them and, potentially, aid in the development of compounds to treat the devastating C9ORF72-related ALS and FTD diseases.

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