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TBK1 haploinsufficiency results in changes in the K63-ubiquitination profiles in brain and fibroblasts from affected and presymptomatic mutation carriers

BACKGROUND: Frontotemporal dementia (FTD) is a neurodegenerative disease, resulting in progressive problems in language and/or behaviour and is often diagnosed before 65 years of age. Ubiquitin positive protein aggregates in the brain are among the key pathologic hallmarks of frontotemporal lobar de...

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Autores principales: Khoshnood, Behzad, Ullgren, Abbe, Laffita-Mesa, Jose, Öijerstedt, Linn, Patra, Kalicharan, Nennesmo, Inger, Graff, Caroline
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Springer Berlin Heidelberg 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9120096/
https://www.ncbi.nlm.nih.gov/pubmed/34800171
http://dx.doi.org/10.1007/s00415-021-10887-x
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author Khoshnood, Behzad
Ullgren, Abbe
Laffita-Mesa, Jose
Öijerstedt, Linn
Patra, Kalicharan
Nennesmo, Inger
Graff, Caroline
author_facet Khoshnood, Behzad
Ullgren, Abbe
Laffita-Mesa, Jose
Öijerstedt, Linn
Patra, Kalicharan
Nennesmo, Inger
Graff, Caroline
author_sort Khoshnood, Behzad
collection PubMed
description BACKGROUND: Frontotemporal dementia (FTD) is a neurodegenerative disease, resulting in progressive problems in language and/or behaviour and is often diagnosed before 65 years of age. Ubiquitin positive protein aggregates in the brain are among the key pathologic hallmarks of frontotemporal lobar degeneration (FTLD) postmortem. The TANK-binding kinase 1 gene (TBK1) is on the list of genes that can contribute to the development of FTD as well as the related neurodegenerative disease amyotrophic lateral sclerosis (ALS). METHODS: In this study, using an array of clinical and neuropathological data combined with biochemical and proteomics assays, we analyze the TBK1 splice-mutation (c.1340 + 1G > A) in a Swedish family with a history of FTD and ALS. We also explore the K63 ubiquitination landscape in post-mortem brain tissue and fibroblast cultures. RESULTS: The intronic (c.1340 + 1G > A) mutation in TBK1 results in haploinsufficiency and affects the activity of the protein in symptomatic and pre-symptomatic mutation carriers. CONCLUSION: Our results suggest that the mutation leads to a significant reduction of TBK1 activity and induce alterations in K63 ubiquitination profile of the cell already in the presymptomatic stages. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s00415-021-10887-x.
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spelling pubmed-91200962022-05-21 TBK1 haploinsufficiency results in changes in the K63-ubiquitination profiles in brain and fibroblasts from affected and presymptomatic mutation carriers Khoshnood, Behzad Ullgren, Abbe Laffita-Mesa, Jose Öijerstedt, Linn Patra, Kalicharan Nennesmo, Inger Graff, Caroline J Neurol Original Communication BACKGROUND: Frontotemporal dementia (FTD) is a neurodegenerative disease, resulting in progressive problems in language and/or behaviour and is often diagnosed before 65 years of age. Ubiquitin positive protein aggregates in the brain are among the key pathologic hallmarks of frontotemporal lobar degeneration (FTLD) postmortem. The TANK-binding kinase 1 gene (TBK1) is on the list of genes that can contribute to the development of FTD as well as the related neurodegenerative disease amyotrophic lateral sclerosis (ALS). METHODS: In this study, using an array of clinical and neuropathological data combined with biochemical and proteomics assays, we analyze the TBK1 splice-mutation (c.1340 + 1G > A) in a Swedish family with a history of FTD and ALS. We also explore the K63 ubiquitination landscape in post-mortem brain tissue and fibroblast cultures. RESULTS: The intronic (c.1340 + 1G > A) mutation in TBK1 results in haploinsufficiency and affects the activity of the protein in symptomatic and pre-symptomatic mutation carriers. CONCLUSION: Our results suggest that the mutation leads to a significant reduction of TBK1 activity and induce alterations in K63 ubiquitination profile of the cell already in the presymptomatic stages. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s00415-021-10887-x. Springer Berlin Heidelberg 2021-11-20 2022 /pmc/articles/PMC9120096/ /pubmed/34800171 http://dx.doi.org/10.1007/s00415-021-10887-x Text en © The Author(s) 2021 https://creativecommons.org/licenses/by/4.0/Open AccessThis 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 http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) .
spellingShingle Original Communication
Khoshnood, Behzad
Ullgren, Abbe
Laffita-Mesa, Jose
Öijerstedt, Linn
Patra, Kalicharan
Nennesmo, Inger
Graff, Caroline
TBK1 haploinsufficiency results in changes in the K63-ubiquitination profiles in brain and fibroblasts from affected and presymptomatic mutation carriers
title TBK1 haploinsufficiency results in changes in the K63-ubiquitination profiles in brain and fibroblasts from affected and presymptomatic mutation carriers
title_full TBK1 haploinsufficiency results in changes in the K63-ubiquitination profiles in brain and fibroblasts from affected and presymptomatic mutation carriers
title_fullStr TBK1 haploinsufficiency results in changes in the K63-ubiquitination profiles in brain and fibroblasts from affected and presymptomatic mutation carriers
title_full_unstemmed TBK1 haploinsufficiency results in changes in the K63-ubiquitination profiles in brain and fibroblasts from affected and presymptomatic mutation carriers
title_short TBK1 haploinsufficiency results in changes in the K63-ubiquitination profiles in brain and fibroblasts from affected and presymptomatic mutation carriers
title_sort tbk1 haploinsufficiency results in changes in the k63-ubiquitination profiles in brain and fibroblasts from affected and presymptomatic mutation carriers
topic Original Communication
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9120096/
https://www.ncbi.nlm.nih.gov/pubmed/34800171
http://dx.doi.org/10.1007/s00415-021-10887-x
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