University of Oulu

Leskelä, S.; Huber, N.; Rostalski, H.; Natunen, T.; Remes, A.M.; Takalo, M.; Hiltunen, M.; Haapasalo, A. C9orf72 Proteins Regulate Autophagy and Undergo Autophagosomal or Proteasomal Degradation in a Cell Type-Dependent Manner. Cells 2019, 8, 1233.

C9orf72 proteins regulate autophagy and undergo autophagosomal or proteasomal degradation in a cell type-dependent manner

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Author: Leskelä, Stina1; Huber, Nadine1; Rostalski, Hannah1;
Organizations: 1A. I. Virtanen Institute for Molecular Sciences, University of Eastern Finland, Neulaniementie 2, 70211 Kuopio, Finland
2Institute of Biomedicine, Yliopistonranta 1E, University of Eastern Finland, 70211 Kuopio, Finland
3Unit of Clinical Neuroscience, Neurology, University of Oulu, P.O. Box 8000, University of Oulu, 90014 Oulu, Finland
4MRC Oulu, Oulu University Hospital, P.O. Box 8000, University of Oulu, 90014 Oulu, Finland
Format: article
Version: published version
Access: open
Online Access: PDF Full Text (PDF, 3.2 MB)
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Language: English
Published: Multidisciplinary Digital Publishing Institute, 2019
Publish Date: 2020-03-19


Dysfunctional autophagy or ubiquitin-proteasome system (UPS) are suggested to underlie abnormal protein aggregation in neurodegenerative diseases. Frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS)-associated C9orf72 is implicated in autophagy, but whether it activates or inhibits autophagy is partially controversial. Here, we utilized knockdown or overexpression of C9orf72 in mouse N2a neuroblastoma cells or cultured neurons to elucidate the potential role of C9orf72 proteins in autophagy and UPS. Induction of autophagy in C9orf72 knockdown N2a cells led to decreased LC3BI to LC3BII conversion, p62 degradation, and formation of LC3-containing autophagosomes, suggesting compromised autophagy. Proteasomal activity was slightly decreased. No changes in autophagy nor proteasomal activity in C9orf72-overexpressing N2a cells were observed. However, in these cells, autophagy induction by serum starvation or rapamycin led to significantly decreased C9orf72 levels. The decreased levels of C9orf72 in serum-starved N2a cells were restored by the proteasomal inhibitor lactacystin, but not by the autophagy inhibitor bafilomycin A1 (BafA1) treatment. These data suggest that C9orf72 undergoes proteasomal degradation in N2a cells during autophagy. Lactacystin significantly elevated C9orf72 levels in N2a cells and neurons, further suggesting UPS-mediated regulation. In rapamycin and BafA1-treated neurons, C9orf72 levels were significantly increased. Altogether, these findings corroborate the previously suggested regulatory role for C9orf72 in autophagy and suggest cell type-dependent regulation of C9orf72 levels via UPS and/or autophagy.

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Series: Cells
ISSN: 2073-4409
ISSN-E: 2073-4409
ISSN-L: 2073-4409
Volume: 8
Issue: 10
Article number: 1233
DOI: 10.3390/cells8101233
Type of Publication: A1 Journal article – refereed
Field of Science: 3124 Neurology and psychiatry
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; 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: © 2019 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (