Abstract
BackgroundFrontotemporal 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).MethodsIn 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.ResultsThe 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.ConclusionOur 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.
Highlights
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
Our results suggest that effects of the TANK-binding kinase 1 gene (TBK1) haploinsufficiency, caused by the p.Ala417* mutation, start already in the pre-symptomatic stage and affect important cellular regulatory mechanisms such as autophagy and K63 ubiquitination in mutation carriers, years before the onset of the disease
Symptoms associated with FTD and/or amyotrophic lateral sclerosis (ALS) was observed in members of the family in three generations (Fig. 1A)
Summary
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. 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. Frontotemporal dementia (FTD) is a fatal neurodegenerative disease that primarily affects the frontal and temporal lobes of the brain, resulting in changes in personality, behaviour and/or language [1]. Frontotemporal lobar degeneration (FTLD) is classified in three major categories of FTLD-TAU, FTLD-TDP and FTLD-FUS, based on detection of the respective protein in the intracellular inclusions. More than 70 variants in the TBK1 gene have been reported as causative for FTD and/or ALS [8]
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