A novel neurodegenerative spectrum disorder in patients with MLKL deficiency

• Verfasst von: Faergeman, Soren L. [VerfasserIn]
• Verfasst von: Evans, Hayley [VerfasserIn]
• Verfasst von: Attfield, Kathrine E. [VerfasserIn]
• Verfasst von: Desel, Christiane Anna-Elisabeth [VerfasserIn]
• Verfasst von: Kuttikkatte, Subita Balaram [VerfasserIn]
• Verfasst von: Sommerlund, Mette [VerfasserIn]
• Verfasst von: Jensen, Lise Torp [VerfasserIn]
• Verfasst von: Frokiaer, Jorgen [VerfasserIn]
• Verfasst von: Friese, Manuel A. [VerfasserIn]
• Verfasst von: Matthews, Paul M. [VerfasserIn]
• Verfasst von: Lüchtenborg, Christian [VerfasserIn]
• Verfasst von: Brügger, Britta [VerfasserIn]
• Verfasst von: Oturai, Annette Bang [VerfasserIn]
• Verfasst von: Dendrou, Calliope A. [VerfasserIn]
• Verfasst von: Fugger, Lars [VerfasserIn]
• Titel: A novel neurodegenerative spectrum disorder in patients with MLKL deficiency
• Verf.angabe: Soren L. Faergeman, Hayley Evans, Kathrine E. Attfield, Christiane Desel, Subita Balaram Kuttikkatte, Mette Sommerlund, Lise Torp Jensen, Jorgen Frokiaer, Manuel A. Friese, Paul M. Matthews, Christian Luchtenborg, Britta Brügger, Annette Bang Oturai, Calliope A. Dendrou and Lars Fugger
• E-Jahr: 2020
• Jahr: 01 May 2020
• Umfang: 13 S.
• Fussnoten: Gesehen am 15.06.2020
• Titel Quelle: Enthalten in: Cell death & disease
• Ort Quelle: London [u.a.] : Nature Publishing Group, 2010
• Jahr Quelle: 2020
• Band/Heft Quelle: 11(2020) Artikel-Nummer 303, 13 Seiten
• ISSN Quelle: 2041-4889
• DOI: doi:10.1038/s41419-020-2494-0
• Datenträger: Online-Ressource
• Sprache: eng
• K10plus-PPN: 1700581090

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.