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 deg...

Full description

Saved in:
Bibliographic Details
Published in:Journal of neurology 2022-06, Vol.269 (6), p.3037-3049
Main Authors: Khoshnood, Behzad, Ullgren, Abbe, Laffita-Mesa, Jose, Öijerstedt, Linn, Patra, Kalicharan, Nennesmo, Inger, Graff, Caroline
Format: Article
Language:English
Subjects:
Amyotrophic lateral sclerosis
Amyotrophic Lateral Sclerosis - diagnosis
Brain - pathology
Dementia disorders
Fibroblasts
Frontotemporal dementia
Frontotemporal Dementia - genetics
Haploinsufficiency
Humans
Medicine
Medicine & Public Health
Mutation
Neurodegeneration
Neurodegenerative diseases
Neurodegenerative Diseases - pathology
Neurology
Neuroradiology
Neurosciences
Original Communication
Protein Serine-Threonine Kinases - genetics
Proteomics
Ubiquitin
Ubiquitination
Citations: Items that this one cites
Items that cite this one
Online Access:Get full text
Tags: Add Tag
No Tags, Be the first to tag this record!
Description
Summary: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.
ISSN:0340-5354
1432-1459
DOI:10.1007/s00415-021-10887-x