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      A novel TBK1 mutation in a family with diverse frontotemporal dementia spectrum disorders

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          Mutations in the TANK-binding kinase 1 ( TBK1) gene have recently been shown to cause frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS). The phenotype is highly variable and has been associated with behavioral variant FTD, primary progressive aphasia, and pure ALS. We describe the clinical, anatomical, and pathological features of a patient who developed corticobasal syndrome (CBS)/progressive nonfluent aphasia (PNFA) overlap. The patient presented with progressive speech difficulties and later developed an asymmetric akinetic–rigid syndrome. Neuroimaging showed asymmetrical frontal atrophy, predominantly affecting the right side. There was a strong family history of neurodegenerative disease with four out of seven siblings developing either dementia or ALS in their 50s and 60s. The patient died at the age of 71 and the brain was donated for postmortem analysis. Histopathological examination showed frontotemporal lobar degeneration TDP-43 type A pathology. Genetic screening did not reveal a mutation in the GRN, MAPT, or C9orf72 genes, but exome sequencing revealed a novel p.E703X mutation in the TBK1 gene. Although segregation data were not available, this loss-of-function mutation is highly likely to be pathogenic because it is predicted to disrupt TBK1/optineurin interaction and impair cellular autophagy. In conclusion, we show that TBK1 mutations can be a cause of an atypical parkinsonian syndrome and screening should be considered in CBS patients with a family history of dementia or ALS.

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          Does corticobasal degeneration exist? A clinicopathological re-evaluation.

          The pathological findings of corticobasal degeneration are associated with several distinct clinical syndromes, and the corticobasal syndrome has been linked with a number of diverse pathologies. We have reviewed all the archival cases in the Queen Square Brain Bank for Neurological Disorders over a 20-year period with either a clinical diagnosis of corticobasal syndrome or pathological diagnosis of corticobasal degeneration in an attempt to identify the main diagnostic pitfalls. Of 19 pathologically confirmed corticobasal degeneration cases, only five had been diagnosed correctly in life (sensitivity=26.3%) and four of these had received an alternative earlier diagnosis. All five of these had a unilateral presentation, clumsy useless limb, limb apraxia and myoclonus, four had cortical sensory impairment and focal limb dystonia and three had an alien limb. Eight cases of corticobasal degeneration had been clinically diagnosed as progressive supranuclear palsy, all of whom had vertical supranuclear palsy and seven had falls within the first 2 years. On the other hand, of 21 cases with a clinical diagnosis of corticobasal syndrome, only five had corticobasal degeneration pathology, giving a positive predictive value of 23.8%; six others had progressive supranuclear palsy pathology, five had Alzheimer's disease and the remaining five had other non-tau pathologies. Corticobasal degeneration can present very commonly with a clinical picture closely resembling classical progressive supranuclear palsy or Richardson's syndrome, and we propose the term corticobasal degeneration-Richardson's syndrome for this subgroup. Cases of corticobasal degeneration-Richardson's syndrome have delayed onset of vertical supranuclear gaze palsy (>3 years after onset of first symptom) and the infrequent occurrence of predominant downgaze abnormalities, both of which can be helpful pointers to their underlying corticobasal degeneration pathology. Fourty-two per cent of corticobasal degeneration cases presented clinically with a progressive supranuclear palsy phenotype and 29% of cases with corticobasal syndrome had underlying progressive supranuclear palsy pathology. In contrast, in the Queen Square Brain Bank archival collection, corticobasal syndrome is a rare clinical presentation of progressive supranuclear palsy occurring in only 6 of the 179 pathologically diagnosed progressive supranuclear palsy cases (3%). Despite these diagnostic difficulties we conclude that corticobasal degeneration is a discrete clinicopathological entity but with a broader clinical spectrum than was originally proposed.
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            Mutations in progranulin (GRN) within the spectrum of clinical and pathological phenotypes of frontotemporal dementia.

            Frontotemporal dementia (FTD) is predominantly a presenile disorder that is characterised by behavioural changes and cognitive impairment, particularly in language and executive functions, and is associated with neurodegeneration in the frontal or temporal cortices, or both. Research into FTD has made many advances over the past 20 years that have important implications for clinical practice. Different clinical variants (ie, behavioural, aphasic, and motor neuron disease variants) are now recognised as part of the clinical spectrum of FTD. Neuropathologically, the disease can be divided into two main pathological subtypes: frontotemporal lobar degeneration (FTLD) with neuronal and glial tau inclusions (FTLD-tau); and FTLD with neuronal inclusions that are positive for ubiquitin (FTLD-U). 20-30% of cases of FTD follow an autosomal dominant pattern of inheritance, and half of which are caused by defects in MAPT, CHMP2B, and VCP. Mutations in the gene that encodes progranulin (GRN) on chromosome 17q21-22 have been identified in patients with hereditary FTD who have tau-negative, ubiquitin-positive inclusions. The recognition of the clinical phenotype associated with more than 50 different mutations in GRN has expanded the clinical knowledge of FTD to include presentations that resemble Alzheimer's disease, Lewy body disease, and corticobasal syndrome, with a variable age at onset (35-89 years) within families. Another recent breakthrough is the identification of the TAR DNA-binding protein (TARDBP; also known as TDP-43) as the main constituent of FTLD-U with mutations in GRN and with mutations in VCP, as well as in FTLD with amyotrophic lateral sclerosis. WHERE NEXT?: To develop therapeutic strategies to prevent FTD or delay its progression we must understand whether the loss of progranulin leads to the accumulation of TARDBP. In this Rapid Review, we focus on the clinical and pathological phenotypes associated with mutations in GRN, and distinguish those from other forms of hereditary FTD. In addition, we discuss the potential association of mutations in GRN on the pathophysiology of FTD with the accumulation of TARDBP.
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              Functional Dissection of the TBK1 Molecular Network

              TANK-binding kinase 1 (TBK1) and inducible IκB-kinase (IKK-i) are central regulators of type-I interferon induction. They are associated with three adaptor proteins called TANK, Sintbad (or TBKBP1) and NAP1 (or TBKBP2, AZI2) whose functional relationship to TBK1 and IKK-i is poorly understood. We performed a systematic affinity purification–mass spectrometry approach to derive a comprehensive TBK1/IKK-i molecular network. The most salient feature of the network is the mutual exclusive interaction of the adaptors with the kinases, suggesting distinct alternative complexes. Immunofluorescence data indicated that the individual adaptors reside in different subcellular locations. TANK, Sintbad and NAP1 competed for binding of TBK1. The binding site for all three adaptors was mapped to the C-terminal coiled-coil 2 region of TBK1. Point mutants that affect binding of individual adaptors were used to reconstitute TBK1/IKK-i-deficient cells and dissect the functional relevance of the individual kinase-adaptor edges within the network. Using a microarray-derived gene expression signature of TBK1 in response virus infection or poly(I∶C) stimulation, we found that TBK1 activation was strictly dependent on the integrity of the TBK1/TANK interaction.

                Author and article information

                Cold Spring Harb Mol Case Stud
                Cold Spring Harb Mol Case Stud
                Cold Spring Harbor Molecular Case Studies
                Cold Spring Harbor Laboratory Press
                June 2019
                : 5
                : 3
                [1 ]Department of Clinical and Movement Neurosciences, Dementia Research Centre, UCL Queen Square Institute of Neurology, London WC1N 3BG, United Kingdom;
                [2 ]Department of Neurodegenerative Disease, Dementia Research Centre, UCL Queen Square Institute of Neurology, London WC1N 3BG, United Kingdom;
                [3 ]Ken and Ruth Davee Department of Neurology, Feinberg School of Medicine, Northwestern University, Chicago, Illinois 60611, USA;
                [4 ]Division of Psychological Medicine and Clinical Neurosciences, MRC Centre for Neuropsychiatric Genetics and Genomics, School of Medicine, Cardiff University, Cardiff CF24 4HQ, United Kingdom;
                [5 ]Department of Neurology, Morriston Hospital, Swansea SA6 6NL, United Kingdom;
                [6 ]Queen Square Brain Bank for Neurological Disorders, UCL Queen Square Institute of Neurology, London WC1N 1PJ, United Kingdom
                Author notes
                Corresponding author: h.morris@

                This article is distributed under the terms of the Creative Commons Attribution-NonCommercial License, which permits reuse and redistribution, except for commercial purposes, provided that the original author and source are credited.

                Page count
                Pages: 10
                Funded by: National Institute for Health Research , open-funder-registry 10.13039/501100000272;
                Funded by: NIHR , open-funder-registry 10.13039/100006662;
                Funded by: Queen Square Biomedical Research Unit in Dementia
                Funded by: University College London Hospitals UCLH , open-funder-registry 10.13039/501100008721;
                Funded by: University College London , open-funder-registry 10.13039/501100000765;
                Funded by: Alzheimer's Research UK
                Funded by: Brain Research Trust
                Funded by: Wolfson Foundation
                Funded by: NIHR Queen Square Dementia Biomedical Research Unit
                Funded by: NIHR UCL/H Biomedical Research Centre
                Funded by: Leonard Wolfson Experimental Neurology Centre (LWENC) Clinical Research Facility
                Funded by: MRC Clinician Scientist Fellowship
                Award ID: MR/M008525/1
                Funded by: NIHR Rare Disease Translational Research Collaboration
                Award ID: BRC149/NS/MH
                Funded by: BRACE , open-funder-registry 10.13039/100011699;
                Funded by: Alzheimer's Research UK senior fellowship
                Funded by: Karin & Sten Mortstedt CBD Solutions
                Funded by: Multiple System Atrophy Trust , open-funder-registry 10.13039/100013128;
                Funded by: Multiple System Atrophy Coalition
                Funded by: Fund Sophia
                Funded by: King Baudouin Foundation , open-funder-registry 10.13039/501100006282;
                Funded by: Alzheimer's Research UK
                Funded by: CBD Solutions
                Funded by: Reta Lila Weston Institute of Neurological Studies
                Funded by: Medical Research Council UK
                Research Report


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