RNA Aptamers Rescue Mitochondrial Dysfunction in a Yeast Model of Huntington's Disease.

Abstract

Huntington's disease (HD) is associated with the misfolding and aggregation of mutant huntingtin harboring an elongated polyglutamine stretch at its N terminus. A distinguishing pathological hallmark of HD is mitochondrial dysfunction. Any strategy that can restore the integrity of the mitochondrial environment should have beneficial consequences for the disease. Specific RNA aptamers were selected that were able to inhibit aggregation of elongated polyglutamine stretch containing mutant huntingtin fragment (103Q-htt). They were successful in reducing the calcium overload, which leads to mitochondrial membrane depolarization in case of HD. In one case, the level of Ca2+ was restored to the level of cells not expressing 103Q-htt, suggesting complete recovery. The presence of aptamers was able to increase mitochondrial mass in cells expressing 103Q-htt, along with rescuing loss of mitochondrial genome. The oxidative damage to the proteome was prevented, which led to increased viability of cells, as monitored by flow cytometry. Thus, the presence of aptamers was able to inhibit aggregation of mutant huntingtin fragment and restore mitochondrial dysfunction in the HD cell model, confirming the advantage of the strategy in a disease-relevant parameter.

• Authors: Kinjal A Patel, Rajeev K Chaudhary, Ipsita Roy
• Journal: Molecular therapy. Nucleic acids (Mol Ther Nucleic Acids) Vol. 12 Pg. 45-56 (Sep 07 2018) ISSN: 2162-2531 [Print] United States
• PMID: 30195782 (Publication Type: Journal Article)
• Copyright: Copyright © 2018 The Authors. Published by Elsevier Inc. All rights reserved.