Functional and structural consequences of TBK1 missense variants in frontotemporal lobar degeneration and amyotrophic lateral sclerosis

Gurfinkel, Yuval; Nicole, Polain; Krushna, Sonar; Penelope, Nice; Ricardo, L. Mancera; Lyn, Rea Sarah

doi:10.1016/j.nbd.2022.105859

Cited by 17 publications

(8 citation statements)

References 67 publications

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“…Recently, nuclear-cytoplasmic trafficking of the histone H1.2 has been found to be essential in the regulation of TBK1 and IRF3 inflammation and antiviral activity ( Wu et al, 2021a ). TBK1 is another gene that causes ALS and FTD, and the TBK1 and FUS pathways might represent converging pathological pathways in disease ( Gurfinkel et al, 2022 ). Interestingly, the Hist1h1c transcript was also found downregulated in the previous FUSDelta14 heterozygous analysis in the spinal cord and in the knockout of FUS in the developmental brain, supporting the role of FUS in regulating this particular gene, at different times and in different tissues.…”

Section: Discussionmentioning

confidence: 99%

Mutation in the FUS nuclear localisation signal domain causes neurodevelopmental and systemic metabolic alterations

Ali,

Godoy-Corchuelo,

Martins-Bach

et al. 2023

Disease Models &Amp; Mechanisms

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Mutations in the ubiquitously expressed DNA/RNA binding protein FUS cause aggressive juvenile forms of amyotrophic lateral sclerosis (ALS). While most FUS mutation studies have focused on motor neuron degeneration, little is known about wider systemic or developmental effects. We studied pleiotropic phenotypes in a physiological knock-in mouse model carrying the pathogenic FUSDelta14 mutation in homozygosity. RNA sequencing of multiple organs aimed to identify pathways altered by the mutant protein in the systemic transcriptome, including metabolic tissues given the link between ALS-FTD and altered metabolism. Few genes were commonly altered across all tissues, and most genes and pathways affected were generally tissue-specific. Phenotypic assessment of mice revealed systemic metabolic alterations related to the pathway changes identified. MRI brain scans and histological characterisation revealed that homozygous FUSDelta14 brains were smaller and displayed significant morphological alterations including a thinner cortex, reduced neuronal number and increased gliosis, which correlated with early cognitive impairment and fatal seizures. We show that the disease aetiology of FUS mutations can include both neurodevelopmental and systemic alterations.

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Section: Discussionmentioning

confidence: 99%

Mutation in the FUS nuclear localisation signal domain causes neurodevelopmental and systemic metabolic alterations

Ali,

Godoy-Corchuelo,

Martins-Bach

et al. 2023

Disease Models &Amp; Mechanisms

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show abstract

“…Recently, nuclear-cytoplasmic trafficking of the histone H1.2 has been found to be essential in the regulation of the TBK1 and IRF3 inflammation and antiviral activity (48). TBK1 is another gene that causes ALS and FTD, which might represent a converging pathological pathway in disease (49). Interestingly the Hist1h1c transcript was also found downregulated in the previous FUSDelta14 heterozygous analysis in the spinal cord and in the knockout of FUS in the developmental brain, supporting the role of FUS in regulating this particular gene, at different times and in different tissues.…”

Section: Discussionmentioning

confidence: 99%

FUSDelta14 mutation impairs normal brain development and causes systemic metabolic alterations

Godoy-Corchuelo

Ali

Martins-Bach

et al. 2023

Preprint

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FUS (Fused in sarcoma) is a ubiquitously expressed RNA binding protein, which is mislocalized and aggregated in some forms of frontotemporal dementia (FTD), whilst mutations in FUS cause aggressive juvenile forms of amyotrophic lateral sclerosis (ALS), as in the case with the FUSDelta14 mutation. Most studies have focused on the role of FUS in motor neuron degeneration, although it is unknown whether FUS mutations affect other cell and tissue types, and the neurodevelopmental impact of FUS mutation on the nervous system is unclear. Here we studied pleiotropic phenotypes in a physiological knock-in mouse model carrying a partially humanised FUSDelta14 mutation in homozygosity. We performed RNA sequencing of six different tissues (frontal cortex, spinal cord, tibialis anterior muscle, white and brown adipose tissue and liver) and found that the genes and pathways affected were generally tissue-specific and showed few commonalities. Phenotypic assessment of homozygous FUSDelta14 mice revealed systemic metabolic alterations related to the pathway changes identified. Homozygous FUSDelta14 brains displayed significant morphological alterations including a thinner cortex, reduced neuronal number and increased gliosis, which correlated with fatal seizures in early adult life. Altogether, our data supports a wide-ranging role for FUS, and suggests that the disease aetiology of FUS mutation can include developmental and pleiotropic phenotypes.

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“…Identifying additional TBK1 mutations that also exhibit increased lysosome localization and Rab7 phosphorylation would also strengthen confidence in the potential disease relevance of the increased TBK1-E696K at lysosomes. However, given that more than 100 TBK1 mutations have so far been discovered in ALS and FTD, it is beyond the scope of this study to systematically test them all (Gurfinkel et al, 2022).…”

Section: Discussionmentioning

confidence: 99%

Lysosomal TBK1 Responds to Amino Acid Availability to Relieve Rab7-Dependent mTORC1 Inhibition

Talaia,

Bentley-DeSousa,

Ferguson

2023

Preprint

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Lysosomes play a pivotal role in coordinating macromolecule degradation and regulating cell growth and metabolism. Despite substantial progress in identifying lysosomal signaling proteins, understanding the pathways that synchronize lysosome functions with changing cellular demands remains incomplete. This study uncovers a role for TANK-binding kinase 1 (TBK1), well known for its role in innate immunity and organelle quality control, in modulating lysosomal responsiveness to nutrients. Specifically, we identify a pool of TBK1 that is recruited to lysosomes in response to elevated amino acid levels. At lysosomes, this TBK1 phosphorylates Rab7 on serine 72. This is critical for alleviating Rab7-mediated inhibition of amino acid-dependent mTORC1 activation. Furthermore, a TBK1 mutant (E696K) associated with amyotrophic lateral sclerosis and frontotemporal dementia constitutively accumulates at lysosomes, resulting in elevated Rab7 phosphorylation and increased mTORC1 activation. This data establishes the lysosome as a site of amino acid regulated TBK1 signaling that is crucial for efficient mTORC1 activation. This lysosomal pool of TBK1 has broader implications for lysosome homeostasis, and its dysregulation could contribute to the pathogenesis of ALS-FTD.

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Functional and structural consequences of TBK1 missense variants in frontotemporal lobar degeneration and amyotrophic lateral sclerosis

Cited by 17 publications

References 67 publications

Mutation in the FUS nuclear localisation signal domain causes neurodevelopmental and systemic metabolic alterations

Mutation in the FUS nuclear localisation signal domain causes neurodevelopmental and systemic metabolic alterations

FUSDelta14 mutation impairs normal brain development and causes systemic metabolic alterations

Lysosomal TBK1 Responds to Amino Acid Availability to Relieve Rab7-Dependent mTORC1 Inhibition

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