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A novel neurodegenerative spectrum disorder in patients with MLKL deficiency

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Title: A novel neurodegenerative spectrum disorder in patients with MLKL deficiency
Authors: Faergeman, SL
Evans, H
Attfield, KE
Desel, C
Kuttikkatte, SB
Sommerlund, M
Jensen, LT
Frokiaer, J
Friese, MA
Matthews, PM
Luchtenborg, C
Brügger, B
Oturai, AB
Dendrou, CA
Fugger, L
Item Type: Journal Article
Abstract: Mixed lineage kinase domain-like (MLKL) is the main executor of necroptosis, an inflammatory form of programmed cell death. Necroptosis is implicated in combating infections, but also in contributing to numerous other clinical conditions, including cardiovascular diseases and neurodegenerative disorders. Inhibition of necroptosis is therefore of therapeutic interest. Here we report two siblings both of whom over the course of 35 years developed a similar progressive, neurodegenerative spectrum disorder characterized by paresis, ataxia and dysarthria. Magnetic resonance imaging of their central nervous system (CNS) revealed severe global cerebral volume loss and atrophy of the cerebellum and brainstem. These brothers are homozygous for a rare haplotype identified by whole genome sequencing carrying a frameshift variant in MLKL, as well as an in-frame deletion of one amino acid in the adjacent fatty acid 2-hydroxylase (FA2H) gene. Functional studies of patient-derived primary cells demonstrated that the variant in MLKL leads to a deficiency of MLKL protein resulting in impairment of necroptosis. Conversely, shotgun lipidomic analysis of the variant in FA2H shows no impact on either the abundance or the enzymatic activity of the encoded hydroxylase. To our knowledge, this is the first report of complete necroptosis deficiency in humans. The findings may suggest that impaired necroptosis is a novel mechanism of neurodegeneration, promoting a disorder that shares some clinical features with primary progressive multiple sclerosis (PPMS) and other neurodegenerative diseases. Importantly, the necroptotic deficiency does not cause symptoms outside the nervous system, nor does it confer susceptibility to infections. Given the current interest in pharmacological inhibition of necroptosis by targeting MLKL and its associated pathways, this strategy should be developed with caution, with careful consideration of the possible development of adverse neurological effects.
Issue Date: 1-May-2020
Date of Acceptance: 7-Apr-2020
URI: http://hdl.handle.net/10044/1/79237
DOI: 10.1038/s41419-020-2494-0
ISSN: 2041-4889
Publisher: Nature Publishing Group
Journal / Book Title: Cell Death and Disease
Volume: 11
Issue: 5
Copyright Statement: © The Author(s) 2020. This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.
Sponsor/Funder: Medical Research Council (MRC)
Merck Serono Ltd
Funder's Grant Number: MR/N026934/1
PO1_5000021752
Keywords: 0601 Biochemistry and Cell Biology
1112 Oncology and Carcinogenesis
Publication Status: Published
Conference Place: England
Article Number: ARTN 303
Online Publication Date: 2020-05-01
Appears in Collections:Faculty of Medicine
Department of Brain Sciences