University of Oulu

Stina Leskelä, Nadine Huber, Dorit Hoffmann, Hannah Rostalski, Anne M. Remes, Mari Takalo, Mikko Hiltunen, Annakaisa Haapasalo, Expression of C9orf72 hexanucleotide repeat expansion leads to formation of RNA foci and dipeptide repeat proteins but does not influence autophagy or proteasomal function in neuronal cells, Biochimica et Biophysica Acta (BBA) - Molecular Cell Research, Volume 1868, Issue 7, 2021, 119021, ISSN 0167-4889,

Expression of C9orf72 hexanucleotide repeat expansion leads to formation of RNA foci and dipeptide repeat proteins but does not influence autophagy or proteasomal function in neuronal cells

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Author: Leskelä, Stina1; Huber, Nadine1; Hoffmann, Dorit1;
Organizations: 1A. I. Virtanen Institute for Molecular Sciences, University of Eastern Finland, P. O. Box 1627, Neulaniementie 2, 70211 Kuopio, Finland
2Unit of Clinical Neuroscience, Neurology, University of Oulu, P. O. Box 8000, FI-90014, Finland
3MRC Oulu, Oulu University Hospital, P. O. Box 8000, FI-90014, University of Oulu, Finland
4Institute of Biomedicine, Yliopistonranta 1E, University of Eastern Finland, 70211 Kuopio, Finland
Format: article
Version: published version
Access: open
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Language: English
Published: Elsevier, 2021
Publish Date: 2021-05-10


C9orf72 hexanucleotide repeat expansion (HRE) is the major genetic cause underpinning frontotemporal lobar degeneration (FLTD) and amyotrophic lateral sclerosis (ALS). C9orf72 HRE-associated pathogenesis involves both loss-of-function, through reduced C9orf72 levels, and gain-of-function mechanisms, including formation of RNA foci and generation of dipeptide repeat (DPR) proteins. In addition, dysfunctional protein degradation pathways, i.e. autophagy and ubiquitin-proteasome system (UPS), are suggested. Our aim was to study the gain-of-function mechanisms in the context of the function of protein degradation pathways as well as the regulation of the DPR proteins through these pathways. To this end, we expressed the pathological HRE in neuronal N2a cells and mouse primary cortical neurons. Protein degradation pathways were modulated to induce or block autophagy or to inhibit UPS. In addition, proteasomal activity was assessed. The C9orf72 HRE-expressing N2a cells and neurons were confirmed to produce RNA foci and DPR proteins, predominantly the Poly-GP proteins. However, the presence of these pathological hallmarks did not result in alterations in autophagy or proteasomal activity in either of the studied cell types. In N2a cells, Poly-GP proteins appeared in soluble forms and Lactacystin-mediated UPS inhibition increased their levels, indicating proteasomal regulation. Similar effects were not observed in cortical neurons, where the Poly-GP proteins formed also higher molecular weight forms. These results suggest a cell type-specific morphology and regulation of the DPR proteins. Further studies in other model systems may shed additional light onto the effects of the C9orf72 HRE on cellular protein degradation pathways and the regulation of the DPR protein levels.

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Series: Biochimica et biophysica acta. Molecular cell research
ISSN: 0167-4889
ISSN-E: 1879-2596
ISSN-L: 0167-4889
Volume: 1868
Issue: 7
Article number: 119021
DOI: 10.1016/j.bbamcr.2021.119021
Type of Publication: A1 Journal article – refereed
Field of Science: 3112 Neurosciences
Funding: This work was supported by the Academy of Finland, under grant numbers 315459, 315460, 307866, and 288659; Yrjö Jahnsson Foundation under grant number 20187070; Päivikki and Sakari Sohlberg Foundation under grant number 5705, Emil Aaltonen Foundation, ALS tutkimuksen tuki ry. registered association; Sigrid Jusélius Foundation; VTR grant 5772816 of Kuopio University Hospital; the Strategic Neuroscience Funding of the University of Eastern Finland; Neurocenter Finland – AlzTrans pilot project. This publication is part of a project that has received funding from the European Union's Horizon 2020 research and innovation programme under the Marie Skłodowska-Curie grant agreement No 740264.
Academy of Finland Grant Number: 315460
Detailed Information: 315460 (Academy of Finland Funding decision)
Copyright information: © 2021 The Author(s). Published by Elsevier B.V. This is an open access article under the CC BY-NC-ND license (