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Brain. 2020 Mar 1;143(3):783-799. doi: 10.1093/brain/awaa039.

CYLD is a causative gene for frontotemporal dementia - amyotrophic lateral sclerosis.

Author information

1
The University of Sydney, Brain and Mind Centre and Central Clinical School, Faculty of Medicine and Health, Camperdown, NSW 2006, Australia.
2
Neuroscience Research Australia, Randwick, NSW 2031, Australia.
3
School of Medical Sciences, University of New South Wales, Sydney, NSW 2052, Australia.
4
Centre for Motor Neuron Disease Research, Department of Biomedical Sciences, Faculty of Medicine and Health Sciences, Macquarie University, North Ryde, NSW 2109, Australia.
5
Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029 USA.
6
Department of Neuroscience, Icahn School of Medicine at Mount Sinai, New York, NY 10029 USA.
7
Dementia Research Centre and Department of Biomedical Sciences, Faculty of Medicine and Health Sciences, Macquarie University, North Ryde, NSW 2109, Australia.
8
SA Clinical Genetics Service, Women's and Children's Hospital, North Adelaide 5006, SA, Australia.
9
Adelaide Medical School, Faculty of Health Sciences, University of Adelaide, Adelaide SA 5005, Australia.
10
Institute of Medical and Veterinary Science, Adelaide, SA 5000, Australia.
11
Department of Neurology, The Queen Elizabeth Hospital, Woodville, SA 5011, Australia.
12
Adelaide Dementia Driving Clinic, Adelaide, SA 5041, Australia.
13
Neurodegenerative Disorders Research Pty Ltd, West Perth, WA 6005, Australia.
14
Department of General Medicine, Royal Adelaide Hospital, Adelaide, SA 5000, Australia.
15
Northcott Neuroscience Laboratory, ANZAC Research Institute, Concord, NSW 2137, Australia.
16
Sydney Medical School, University of Sydney, Camperdown, NSW 2050, Australia.
17
Molecular Medicine Laboratory, Concord Hospital, Concord, NSW 2137, Australia.
18
Prince of Wales Clinical School, University of New South Wales, Sydney, NSW 2052, Australia.
19
Institute of Genetic Medicine, Newcastle University, Newcastle upon Tyne, NE1 3BZ, UK.
20
Population Health and Immunity Division, Walter and Eliza Hall Institute of Medical Research, Parkville, VIC 3052, Australia.
21
Epilepsy Research Centre, Department of Medicine, The University of Melbourne, Austin Health, Heidelberg, VIC 3084, Australia.
22
Department of Medical Biology, The University of Melbourne, Parkville, VIC 3052, Australia.
23
University of Massachusetts Medical School, Worcester, MA 01655, USA.
24
The University of Sydney, Brain and Mind Centre and School of Psychology, Camperdown, NSW 2006, Australia.
25
ARC Centre of Excellence in Cognition and its Disorders, Sydney, NSW, Australia.
26
UK Dementia Research Institute, Department of Basic and Clinical Neuroscience, Institute of Psychiatry, Psychology and Neuroscience, Maurice Wohl Clinical Neuroscience Institute, King's College London, London SE5 9RX, UK.
27
Department of Biochemistry and Genetics, La Trobe Institute for Molecular Science, Bundoora, VIC 3083, Australia.

Abstract

Frontotemporal dementia and amyotrophic lateral sclerosis are clinically and pathologically overlapping disorders with shared genetic causes. We previously identified a disease locus on chromosome 16p12.1-q12.2 with genome-wide significant linkage in a large European Australian family with autosomal dominant inheritance of frontotemporal dementia and amyotrophic lateral sclerosis and no mutation in known amyotrophic lateral sclerosis or dementia genes. Here we demonstrate the segregation of a novel missense variant in CYLD (c.2155A>G, p.M719V) within the linkage region as the genetic cause of disease in this family. Immunohistochemical analysis of brain tissue from two CYLD p.M719V mutation carriers showed widespread glial CYLD immunoreactivity. Primary mouse neurons transfected with CYLDM719V exhibited increased cytoplasmic localization of TDP-43 and shortened axons. CYLD encodes a lysine 63 deubiquitinase and CYLD cutaneous syndrome, a skin tumour disorder, is caused by mutations that lead to reduced deubiquitinase activity. In contrast with CYLD cutaneous syndrome-causative mutations, CYLDM719V exhibited significantly increased lysine 63 deubiquitinase activity relative to the wild-type enzyme (paired Wilcoxon signed-rank test P = 0.005). Overexpression of CYLDM719V in HEK293 cells led to more potent inhibition of the cell signalling molecule NF-κB and impairment of autophagosome fusion to lysosomes, a key process in autophagy. Although CYLD mutations appear to be rare, CYLD's interaction with at least three other proteins encoded by frontotemporal dementia and/or amyotrophic lateral sclerosis genes (TBK1, OPTN and SQSTM1) suggests that it may play a central role in the pathogenesis of these disorders. Mutations in several frontotemporal dementia and amyotrophic lateral sclerosis genes, including TBK1, OPTN and SQSTM1, result in a loss of autophagy function. We show here that increased CYLD activity also reduces autophagy function, highlighting the importance of autophagy regulation in the pathogenesis of frontotemporal dementia and amyotrophic lateral sclerosis.

KEYWORDS:

CYLD; autophagy; deubiquitinase; genome-wide linkage analysis; whole-exome sequencing

PMID:
32185393
PMCID:
PMC7089666
[Available on 2021-03-01]
DOI:
10.1093/brain/awaa039

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