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Int. J. Mol. Sci. 2017, 18(10), 2093; doi:10.3390/ijms18102093

CRISPR-Cas9 Mediated Telomere Removal Leads to Mitochondrial Stress and Protein Aggregation

1
Division of Pharmacology, Department of Molecular Cell Biology, Sungkyunkwan University School of Medicine, Samsung Biomedical Research Institute, Suwon, Gyeonggi-do 440-746, Korea
2
College of Pharmacy, Chosun University, Gwangju 501-759, Korea
3
Single Cell Network Research Center, Sungkyunkwan University School of Medicine, Suwon, Gyeonggi-do 440-746, Korea
*
Authors to whom correspondence should be addressed.
Received: 28 August 2017 / Revised: 29 September 2017 / Accepted: 30 September 2017 / Published: 3 October 2017
(This article belongs to the Special Issue Genome Editing 2017)
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Abstract

Aging is considered the major risk factor for neurodegenerative diseases including Parkinson’s disease (PD). Telomere shortening is associated with cellular senescence. In this regard, pharmacological or genetic inhibition of telomerase activity has been used to model cellular aging. Here, we employed CRISPR-Cas9 technology to instantly remove the telomere to induce aging in a neuroblastoma cell line. Expression of both Cas9 and guide RNA targeting telomere repeats ablated the telomere, leading to retardation of cell proliferation. Instant deletion of telomere in SH-SY5Y cells impaired mitochondrial function with diminished mitochondrial respiration and cell viability. Supporting the pathological relevance of cell aging by CRISPR-Cas9 mediated telomere removal, alterations were observed in the levels of PD-associated proteins including PTEN-induced putative kinase 1, peroxisome proliferator-activated receptor γ coactivator 1-α, nuclear respiratory factor 1, parkin, and aminoacyl tRNA synthetase complex interacting multifunctional protein 2. Significantly, α-synuclein expression in the background of telomere removal led to the enhancement of protein aggregation, suggesting positive feed-forward interaction between aging and PD pathogenesis. Collectively, our results demonstrate that CRISPR-Cas9 can be used to efficiently model cellular aging and PD. View Full-Text
Keywords: CRISPR-Cas9; telomere; aging; mitochondria; Parkinson’s disease CRISPR-Cas9; telomere; aging; mitochondria; Parkinson’s disease
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This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. (CC BY 4.0).

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MDPI and ACS Style

Kim, H.; Ham, S.; Jo, M.; Lee, G.H.; Lee, Y.-S.; Shin, J.-H.; Lee, Y. CRISPR-Cas9 Mediated Telomere Removal Leads to Mitochondrial Stress and Protein Aggregation. Int. J. Mol. Sci. 2017, 18, 2093.

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