A novel neurodegenerative spectrum disorder in patients with MLKL deficiency
| Autor: | Jørgen Frøkiær, Christiane Desel, Britta Brügger, Paul M. Matthews, Lise T. Jensen, Soren L. Faergeman, Calliope A. Dendrou, Annette Bang Oturai, Hayley G. Evans, Christian Lüchtenborg, Mette Sommerlund, Subita Balaram Kuttikkatte, Lars Fugger, Manuel A. Friese, Kathrine E. Attfield |
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| Přispěvatelé: | Medical Research Council (MRC), Merck Serono Ltd |
| Jazyk: | angličtina |
| Rok vydání: | 2020 |
| Předmět: |
Nervous system
Cancer Research Programmed cell death Ataxia Necroptosis Immunology Central nervous system Apoptosis 0601 Biochemistry and Cell Biology Bioinformatics Article Frameshift mutation 03 medical and health sciences Cellular and Molecular Neuroscience 0302 clinical medicine Atrophy medicine Animals Humans 1112 Oncology and Carcinogenesis lcsh:QH573-671 Neurodegeneration Phosphorylation 030304 developmental biology 0303 health sciences lcsh:Cytology business.industry Neurodegenerative diseases Cell Biology medicine.disease MAP Kinase Kinase Kinases 3. Good health medicine.anatomical_structure Receptor-Interacting Protein Serine-Threonine Kinases medicine.symptom business Protein Kinases 030217 neurology & neurosurgery |
| Zdroj: | Cell Death & Disease Faergeman, S L, Evans, H, Attfield, K E, Desel, C, Kuttikkatte, S B, Sommerlund, M, Jensen, L T, Frokiaer, J, Friese, M A, Matthews, P M, Luchtenborg, C, Brügger, B, Oturai, A B, Dendrou, C A & Fugger, L 2020, ' A novel neurodegenerative spectrum disorder in patients with MLKL deficiency ', Cell Death and Disease, vol. 11, no. 5, 303 . https://doi.org/10.1038/s41419-020-2494-0 Faergeman, S L, Evans, H, Attfield, K E, Desel, C, Kuttikkatte, S B, Sommerlund, M, Jensen, L T, Frokiaer, J, Friese, M A, Matthews, P M, Luchtenborg, C, Brügger, B, Oturai, A B, Dendrou, C A & Fugger, L 2020, ' A novel neurodegenerative spectrum disorder in patients with MLKL deficiency ', Cell Death and Disease, vol. 11, 303 . https://doi.org/10.1038/s41419-020-2494-0 Cell Death and Disease, Vol 11, Iss 5, Pp 1-13 (2020) |
| ISSN: | 2041-4889 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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