TBK1 is associated with ALS and ALS-FTD in Sardinian patients

Borghero, Giuseppe; Pugliatti, Maura; Marrosu, Francesco; Marrosu, Maria Giovanna; Murru, Maria Rita; Floris, Gianluca; Cannas, Antonino; Occhineri, Patrizia; Cau, Tea B.; Loi, Daniela; Ticca, Anna; Traccis, S.; Manera, Umberto; Canosa, Antonio; Moglia, Cristina; Calvo, Andrea; Barberis, Marco; Brunetti, Maura; Gibbs, J. Raphael; Renton, Alan E.; Errichiello, Edoardo; Żołędziewska, Magdalena; Mulas, Antonella; Qian, Yong; Din, Jun; Pliner, Hannah A.; Traynor, Bryan J.; Chiò, Adriano; Logullo, Francesco; Simone, Isabella Laura; Logroscino, Giancarlo; Salvi, Fabrizio; Bartolomei, Ilaria; Capasso, Margherita; Caponnetto, Claudia; Mandich, P; Mancardi, Gianluigi; Origone, Paola; Conforti, Francesca Luisa; Vita, Giuseppe; Messina, Sonia; Russo, Massimo; Mora, Gabriele; Marinou, Kalliopi; Sideri, Riccardo; Lunetta, Christian; Penco, Silvana; Mosca, Lorena; Lauria, Giuseppe; Corbo, Massimo; Riva, Nilo; Carrera, Paola; Volanti, Paolo; Tremolizzo, Lucio; Ferrarese, Carlo; Fini, Nicola; Fasano, Antonio; Monsurrò, Maria Rosaria; Tedeschi, Gioacchino; Trojsi, Francesca; Piccirillo, Giovanni; Cristillo, Viviana; Mazzini, Letizia; D’Alfonso, Sandra; Bersano, Anna; Corrado, Lucia; Bagarotti, Alessandra; Bella, Vincenzo La; Spataro, Rossella; Colletti, Tiziana; Sabatelli, Mario; Zollino, Marcella; Conte, Amelia; Luigetti, Marco; Lattante, Serena; Marangi, Giuseppe; Santarelli, Marialuisa; Petrucci, Antonio; Giannini, F.; Battistini, Stefania; Ricci, Claudia; Benigni, Michele; Restagno, Gabriella; Casale, Federico; Marrali, Giuseppe; Fuda, Giuseppe; Ossola, Irene; Cammarosano, Stefania; Ilardi, Antonio; Bertuzzo, Davide; Tanel, Raffaella; Pisano, Fabrizio; Costantino, E; Pani, Carla; Puddu, Roberta; Caredda, Carla; Piras, Valeria; Tranquilli, Stefania; Cuccu, Stefania; Corongiu, Daniela; Melis, Maurizio; Milia, Antonio; Pirisi, Angelo; Parish, Leslie D.; Ortu, Enzo

doi:10.1016/j.neurobiolaging.2016.03.028

Cited by 46 publications

(30 citation statements)

References 13 publications

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“…The advent of NGS has in the last decade led to an era of inexpensive, high-throughput DNA sequencing of large numbers of genes in a single reaction, thus facilitating the discovery of novel disease genes and variants (6, 10, 33–35). …”

Section: Next Generation Sequencingmentioning

confidence: 99%

Next-generation sequencing in neuromuscular diseases

Efthymiou¹,

Manole²,

Houlden³

2016

Current Opinion in Neurology

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Purpose of review Neuromuscular diseases are clinically and genetically heterogeneous and probably contains the greatest proportion of causative Mendelian defects than any other group of conditions. These disorders affect muscle and/or nerves with neonatal, childhood or adulthood onset, with significant disability and early mortality. Along with heterogeneity, unidentified and often very large genes, require complementary and comprehensive methods in routine molecular diagnosis. Inevitably this leads to increased diagnostic delays and challenges in the interpretation of genetic variants. Recent findings The application of next-generation sequencing, as a research and diagnostic strategy has made significant progress into solving many of these problems. The analysis of these data is by no means simple and the clinical input is essential to interpret results. Summary In this review, we describe using examples the recent advances in the genetic diagnosis of neuromuscular disorders, in research and clinical practice and the latest developments that are underway in NGS. We also discuss the latest collaborative initiatives such as the Genomics England genome sequencing project that combine rare disease clinical phenotyping with genomics, with the aim of defining the vast majority of rare disease genes in patients as well as modifying risks and pharmacogenomics factors.

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Section: Next Generation Sequencingmentioning

confidence: 99%

Next-generation sequencing in neuromuscular diseases

Efthymiou¹,

Manole²,

Houlden³

2016

Current Opinion in Neurology

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“…The TBK1 gene is comprised of 21 exons, 20 of which are coding, and these were amplified using polymerase chain reaction (PCR) in a thermal cycler (G-Storm, Somerton, UK). Primers for TBK1 exons 2,4,5,6,7,8,9,10,11,16,[17][18]19-20 and 21 were those described previously [21]. Primers for TBK1 exons 3, 12, 13 and 14-15 were re-designed using Primer Blast (NCBI; Table S1).…”

Section: Methodsmentioning

confidence: 99%

“…Mutations in TANK binding kinase gene (TBK1) located on chromosome 12 (12q14.2), were first linked to ALS in 2015 [4,5]. To date, multiple loss-of-function (LoF) and missense TBK1 variants have been reported and the majority of these are associated with either ALS, ALS-FTD or FTD [6][7][8][9][10][11][12][13]. However, mutations in TBK1 have also been identified in cases of progressive bulbar palsy, primary progressive aphasia (PPA), monoparesis, progressive supranuclear palsy-like and cerebellar syndromes, as well as in cases of early onset Alzheimer's disease and unspecified dementia [5,9,14,15].…”

Section: Introductionmentioning

confidence: 99%

Neuropathological characterization of a novel TANK binding kinase (TBK1) gene loss of function mutation associated with amyotrophic lateral sclerosis

Weinreich

Shepheard

Verber

et al. 2019

Neuropathology Appl Neurobio

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2020) Neuropathology and Applied Neurobiology 46, 279-291 Neuropathological characterization of a novel TANK binding kinase (TBK1) gene loss of function mutation associated with amyotrophic lateral sclerosis Aims: Mutations in TANK binding kinase gene (TBK1) are causative in amyotrophic lateral sclerosis (ALS), however correlations between clinical features and TBK1 mutations have not been fully elucidated. We aimed to identify and compare TBK1 mutations to clinical features in a cohort of ALS patients from Northern England. Methods: TBK1 mutations were analysed in 290 ALS cases. Immunohistochemistry was performed in brain and spinal cord of one case with a novel in-frame deletion. Results: Seven TBK1 variants were identified, including one novel in-frame deletion (p.85delIle). In silico analysis and literature suggested four variants were pathogenic, and three were variants of uncertain significance or benign.Post-mortem immunohistochemistry established an individual with the novel in-frame deletion had classical ALS and Type B FTLD-TDP pathology, with no changes in TBK1 staining or interferon regulatory factor IRF3. Conclusions: TBK1 mutations were present in 1.38% of our cohort, and screening showed no clear genotype-phenotype associations compared to other genetic and sporadic ALS cases. TBK1 immunohistochemistry was consistent with previously published literature and we are the first to show no differential expression of interferon regulatory factor IRF3, a downstream effector of TBK1 in the immune pathway, in the TBK1-mutant tissue, compared to controls.

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“…Of the three novel tau interacting kinases identified, we further validated TBK1, a pleiotropic serine threonine kinase belonging to the non-canonical IKK family of kinases (29,30), best characterized for its role in innate immunity signaling (31)(32)(33)(34)(35), selective autophagy pathways (36)(37)(38), energy metabolism (39,40), tumorigenesis (41), and microtubule dynamics (42). Notably, genetic studies have also identified mutations in TBK1 gene as causal for neurodegenerative diseases including frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS) (43)(44)(45)(46)(47). However, a role for TBK1 in modifying tau phosphorylation and toxicity in AD and other tauopathies is not known.…”

Section: Introductionmentioning

confidence: 94%

TBK1 interacts with tau and enhances neurodegeneration in tauopathy

Abreha

Ojelade

Dammer

et al. 2020

Preprint

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Running title: TBK1 is a tau-directed kinase Key words: TANK-binding kinase 1 (TBK1), microtubule associated protein tau (MAPT), neurofibrillary tangles (NFTs), Alzheimer's disease (AD), familial frontotemporal dementia and parkinsonism linked to chromosome 17 (FTDP-17), co-immunoprecipitation (co-IP), mass spectrometry (MS), post-translational modification (PTM), Drosophila, IκB kinase (IKK) ABSTRACT One of the defining pathological features of Alzheimer's Disease (AD) is the deposition of neurofibrillary tangles (NFTs) composed of hyperphosphorylated tau in the brain. Aberrant activation of kinases in AD has been suggested to enhance phosphorylation and toxicity of tau, making the responsible taudirected kinases attractive therapeutic targets. The full complement of tau interacting kinases in AD brain and their activity in disease remains incompletely defined.Here, immunoaffinity enrichment coupled with mass spectrometry (MS) identified TANKbinding kinase 1 (TBK1) as a tau-interacting partner in human AD cortical brain tissues. We validated this interaction in both human AD and familial frontotemporal dementia and parkinsonism linked to chromosome 17 (FTDP-17) caused by mutations in MAPT (R406W) postmortem brain tissues as well as human cell lines. Further, we document increased TBK1 activity in both AD and FTDP-17 and map the predominant TBK1 phosphorylation sites on tau based on in vitro kinase assays coupled to MS. Lastly, in a Drosophila tauopathy model, activating expression of a conserved TBK1 ortholog triggers tau hyperphosphorylation and enhanced neurodegeneration, whereas knockdown had the reciprocal effect, suppressing tau toxicity. Collectively, our findings suggest that increased TBK1 activity may promote tau hyperphosphorylation and neuronal loss in AD and related tauopathies.

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TBK1 is associated with ALS and ALS-FTD in Sardinian patients

Cited by 46 publications

References 13 publications

Next-generation sequencing in neuromuscular diseases

Next-generation sequencing in neuromuscular diseases

Neuropathological characterization of a novel TANK binding kinase (TBK1) gene loss of function mutation associated with amyotrophic lateral sclerosis

TBK1 interacts with tau and enhances neurodegeneration in tauopathy

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