University of Oulu

Huber, N., Hoffmann, D., Giniatullina, R., Rostalski, H., Leskelä, S., Takalo, M., Natunen, T., Solje, E., Remes, A. M., Giniatullin, R., Hiltunen, M., & Haapasalo, A. (2022). C9orf72 hexanucleotide repeat expansion leads to altered neuronal and dendritic spine morphology and synaptic dysfunction. Neurobiology of Disease, 162, 105584. https://doi.org/10.1016/j.nbd.2021.105584

C9orf72 hexanucleotide repeat expansion leads to altered neuronal and dendritic spine morphology and synaptic dysfunction

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Author: Huber, Nadine1; Hoffmann, Dorit1; Giniatullina, Raisa2;
Organizations: 1Molecular Neurodegeneration group, A.I. Virtanen Institute for Molecular Sciences, University of Eastern Finland, Neulaniementie 2, 70211 Kuopio, Finland
2Molecular Pain Research group, A.I. Virtanen Institute for Molecular Sciences, University of Eastern Finland, Neulaniementie 2, 70211 Kuopio, Finland
3Institute of Biomedicine, University of Eastern Finland, Yliopistonranta 1E, 70211 Kuopio, Finland
4Institute of Clinical Medicine - Neurology, University of Eastern Finland, Yliopistonranta 1 C, 70211 Kuopio, Finland
5Neuro Center, Neurology, Kuopio University Hospital, P. O. Box 100, FI-70029 KYS, Finland
6Medical Research Center, Oulu University Hospital, P. O. Box 8000, FI-90014 University of Oulu, Finland
7Unit of Clinical Neuroscience, Neurology, University of Oulu, P. O. Box 8000, FI-90014 University of Oulu, Finland
Format: article
Version: published version
Access: open
Online Access: PDF Full Text (PDF, 8.3 MB)
Persistent link: http://urn.fi/urn:nbn:fi-fe2022051134399
Language: English
Published: Elsevier, 2022
Publish Date: 2022-08-08
Description:

Abstract

Frontotemporal lobar degeneration (FTLD) comprises a heterogenous group of progressive neurodegenerative syndromes. To date, no validated biomarkers or effective disease-modifying therapies exist for the different clinical or genetic subtypes of FTLD. The most common genetic cause underlying FTLD and amyotrophic lateral sclerosis (ALS) is a hexanucleotide repeat expansion in the C9orf72 gene (C9-HRE). FTLD is accompanied by changes in several neurotransmitter systems, including the glutamatergic, GABAergic, dopaminergic, and serotonergic systems and many clinical symptoms can be explained by disturbances in these systems. Here, we aimed to elucidate the effects of the C9-HRE on synaptic function, molecular composition of synapses, and dendritic spine morphology. We overexpressed the pathological C9-HRE in cultured E18 mouse primary hippocampal neurons and characterized the pathological, morphological, and functional changes by biochemical methods, confocal microscopy, and live cell calcium imaging. The C9-HRE-expressing neurons were confirmed to display the pathological RNA foci and DPR proteins. C9-HRE expression led to significant changes in dendritic spine morphologies, as indicated by decreased number of mushroom-type spines and increased number of stubby and thin spines, as well as diminished neuronal branching. These morphological changes were accompanied by concomitantly enhanced susceptibility of the neurons to glutamate-induced excitotoxicity as well as augmented and prolonged responses to excitatory stimuli by glutamate and depolarizing potassium chloride as compared to control neurons. Mechanistically, the hyperexcitation phenotype in the C9-HRE-expressing neurons was found to be underlain by increased activity of extrasynaptic GluN2B-containing N-methyl-d-aspartate (NMDA) receptors. Our results are in accordance with the idea suggesting that C9-HRE is associated with enhanced excitotoxicity and synaptic dysfunction. Thus, therapeutic interventions targeted to alleviate synaptic disturbances might offer efficient avenues for the treatment of patients with C9-HRE-associated FTLD.

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Series: Neurobiology of disease
ISSN: 0969-9961
ISSN-E: 1095-953X
ISSN-L: 0969-9961
Volume: 162
Article number: 105584
DOI: 10.1016/j.nbd.2021.105584
OADOI: https://oadoi.org/10.1016/j.nbd.2021.105584
Type of Publication: A1 Journal article – refereed
Field of Science: 3124 Neurology and psychiatry
3112 Neurosciences
Subjects:
Funding: This project was supported by the grants of Academy of Finland, grant number 315459 (AH), 315460 (AMR), 307866 (MH), and 330178 (MT), Sigrid Jusélius Foundation (MH, ES), the Strategic Neuroscience Funding of the University of Eastern Finland (AH, MH), Yrjö Jahnsson Foundation (AH), Päivikki and Sakari Sohlberg Foundation (AH), Finnish Brain Foundation (ES), Orion Research Foundation (ES), Instrumentarium Science Foundation (ES), and ALS tutkimuksen tuki ry. registered association (NH, SL, HR). NH, SL, and HR are or were PhD students in the Doctoral Program of Molecular Medicine (DPMM) and/or GenomMed (HR) of the University of Eastern Finland (Kuopio, Finland). 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. This study is also part of the research activities of the Finnish FTD Research Network (FinFTD).
Academy of Finland Grant Number: 315460
Detailed Information: 315460 (Academy of Finland Funding decision)
Copyright information: © 2021 The Authors. Published by Elsevier Inc. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).
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