University of Oulu

Leskelä, S., Hoffmann, D., Rostalski, H. et al. FTLD Patient–Derived Fibroblasts Show Defective Mitochondrial Function and Accumulation of p62. Mol Neurobiol 58, 5438–5458 (2021).

FTLD patient–derived fibroblasts show defective mitochondrial function and accumulation of p62

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Author: Leskelä, Stina1; Hoffmann, Dorit1; Rostalski, Hannah1;
Organizations: 1A. I. Virtanen Institute for Molecular Sciences, University of Eastern Finland, Neulaniementie 2, 70211 Kuopio, Finland
2Institute of Biomedicine, University of Eastern Finland, Yliopistonranta 1E, 70211 Kuopio, Finland
3Neuro Center, Neurology, Kuopio University Hospital, 70029 Kuopio, Finland
4Neuro Center, Neurosurgery, Kuopio University Hospital, 70029 Kuopio, Finland
5Institute of Clinical Medicine – Neurosurgery, University of Eastern Finland, Yliopistonranta 1C, 70211 Kuopio, Finland
6Institute of Clinical Medicine – Neurology, University of Eastern Finland, Yliopistonranta 1C, 70211 Kuopio, Finland
7Unit of Clinical Neuroscience, Neurology, University of Oulu, P.O. Box 8000, 90014 Oulu, Finland
8MRC Oulu, Oulu University Hospital, P.O. Box 8000, 90014 Oulu, Finland
Format: article
Version: published version
Access: open
Online Access: PDF Full Text (PDF, 7.3 MB)
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Language: English
Published: Springer Nature, 2021
Publish Date: 2022-02-02


Frontotemporal lobar degeneration (FTLD) is a clinically, genetically, and neuropathologically heterogeneous group of neurodegenerative syndromes, leading to progressive cognitive dysfunction and frontal and temporal atrophy. C9orf72 hexanucleotide repeat expansion (C9-HRE) is the most common genetic cause of FTLD, but pathogenic mechanisms underlying FTLD are not fully understood. Here, we compared cellular features and functional properties, especially related to protein degradation pathways and mitochondrial function, of FTLD patient–derived skin fibroblasts from C9-HRE carriers and non-carriers and healthy donors. Fibroblasts from C9-HRE carriers were found to produce RNA foci, but no dipeptide repeat proteins, and they showed unchanged levels of C9orf72 mRNA transcripts. The main protein degradation pathways, the ubiquitin–proteasome system and autophagy, did not show alterations between the fibroblasts from C9-HRE-carrying and non-carrying FTLD patients and compared to healthy controls. An increase in the number and size of p62-positive puncta was evident in fibroblasts from both C9-HRE carriers and non-carriers. In addition, several parameters of mitochondrial function, namely, basal and maximal respiration and respiration linked to ATP production, were significantly reduced in the FTLD patient–derived fibroblasts from both C9-HRE carriers and non-carriers. Our findings suggest that FTLD patient–derived fibroblasts, regardless of whether they carry the C9-HRE expansion, show unchanged proteasomal and autophagic function, but significantly impaired mitochondrial function and increased accumulation of p62 when compared to control fibroblasts. These findings suggest the possibility of utilizing FTLD patient–derived fibroblasts as a platform for biomarker discovery and testing of drugs targeted to specific cellular functions, such as mitochondrial respiration..

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Series: Molecular neurobiology
ISSN: 0893-7648
ISSN-E: 0893-7648
ISSN-L: 0893-7648
Volume: 58
Issue: 11
Pages: 5438 - 5458
DOI: 10.1007/s12035-021-02475-x
Type of Publication: A1 Journal article – refereed
Field of Science: 3112 Neurosciences
Funding: Open access funding provided by University of Eastern Finland (UEF) including Kuopio University Hospital. This study was supported by the Academy of Finland, grant nos. 315459 (A.H.), 315460 (A.M.R.), and 307866 (M.H.); Yrjö Jahnsson Foundation (A.H.); Päivikki and Sakari Sohlberg Foundation (A.H.); Emil Aaltonen Foundation (S.L.); ALS tutkimuksen tuki ry. registered association (H.R., S.L., N.H.); Sigrid Jusélius Foundation (M.H., E.S.); Finnish Brain Foundation (E.S.); Instrumentarium Science Foundation (E.S.); Orion Research Foundation (E.S.); the Strategic Neuroscience Funding of the University of Eastern Finland (A.H., M.H.). H.R., S.L., N.H., and R.W. are supported by the University of Eastern Finland (UEF) Doctoral Program in Molecular Medicine (DPMM) and GenomMed. This publication is part of a project that has received funding from the European Union’s Horizon 2020 research and innovation program 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: © The Author(s) 2021. This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit