Bi-allelic variants in RNF170 are associated with hereditary spastic paraplegia
| Autor: | Jennifer Reichbauer, Neda Shahmohammadibeni, Matias Wagner, Selina Reich, Rebecca Schüle, Sergio Padilla-Lopez, Rim Amouri, Wolfgang Müller-Felber, Ina Gehweiler, Christoph Kernstock, Michael C. Kruer, Ege Ozkan, Katharina Vill, Daniel P. S. Osborn, Ehsan Ghayoor Karimiani, Benedikt Hölbling, Yalda Jamshidi, Somayeh Bakhtiari, Maryam M. Hockley, Reza Maroofian, Stephan Züchner, Ulrike Ulmer, Fayçal Hentati, Thomas Schwarzmayr, Hossein Darvish, Abbas Tafakhori, Juliane Winkelmann, Reza Boostani, Maike Nagel |
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| Jazyk: | angličtina |
| Předmět: |
0301 basic medicine
Male General Physics and Astronomy Inositol 1 4 5-Trisphosphate Endoplasmic Reticulum chemistry.chemical_compound 0302 clinical medicine metabolism [Endoplasmic Reticulum] cytology [Skin] genetics [Endoplasmic Reticulum-Associated Degradation] metabolism [Inositol 1 4 5-Trisphosphate] Inositol 1 4 5-Trisphosphate Receptors metabolism [Calcium] Inositol lcsh:Science Receptor Child Zebrafish Skin genetics [Ubiquitin-Protein Ligases] Neurons Gene knockdown RNF170 protein human Multidisciplinary biology Medical genetics High-Throughput Nucleotide Sequencing Endoplasmic Reticulum-Associated Degradation Middle Aged Ubiquitin ligase Cell biology ddc metabolism [Neurons] Child Preschool Gene Knockdown Techniques Female ddc:500 Signal transduction medicine.symptom metabolism [Fibroblasts] Signal Transduction Adult Adolescent Hereditary spastic paraplegia Science Ubiquitin-Protein Ligases Primary Cell Culture General Biochemistry Genetics and Molecular Biology Article 03 medical and health sciences genetics [Spastic Paraplegia Hereditary] Cell Line Tumor medicine Animals Humans Motor neuron disease Cerebellar ataxia Spastic Paraplegia Hereditary Endoplasmic reticulum General Chemistry Fibroblasts medicine.disease metabolism [Inositol 1 4 5-Trisphosphate Receptors] nervous system diseases 030104 developmental biology chemistry metabolism [Spastic Paraplegia Hereditary] biology.protein Diseases of the nervous system lcsh:Q Calcium Spinocerebellar ataxia 030217 neurology & neurosurgery |
| Zdroj: | Nature Communications Nat. Commun. 10:4790 (2019) Nature Communications, Vol 10, Iss 1, Pp 1-13 (2019) Nature Communications 10(1), 4790 (2019). doi:10.1038/s41467-019-12620-9 |
| ISSN: | 2041-1723 |
| DOI: | 10.1038/s41467-019-12620-9 |
| Popis: | Alterations of Ca2+ homeostasis have been implicated in a wide range of neurodegenerative diseases. Ca2+ efflux from the endoplasmic reticulum into the cytoplasm is controlled by binding of inositol 1,4,5-trisphosphate to its receptor. Activated inositol 1,4,5-trisphosphate receptors are then rapidly degraded by the endoplasmic reticulum-associated degradation pathway. Mutations in genes encoding the neuronal isoform of the inositol 1,4,5-trisphosphate receptor (ITPR1) and genes involved in inositol 1,4,5-trisphosphate receptor degradation (ERLIN1, ERLIN2) are known to cause hereditary spastic paraplegia (HSP) and cerebellar ataxia. We provide evidence that mutations in the ubiquitin E3 ligase gene RNF170, which targets inositol 1,4,5-trisphosphate receptors for degradation, are the likely cause of autosomal recessive HSP in four unrelated families and functionally evaluate the consequences of mutations in patient fibroblasts, mutant SH-SY5Y cells and by gene knockdown in zebrafish. Our findings highlight inositol 1,4,5-trisphosphate signaling as a candidate key pathway for hereditary spastic paraplegias and cerebellar ataxias and thus prioritize this pathway for therapeutic interventions. Disturbances in IP3 receptor-mediated release of Ca2+ from the endoplasmatic reticulum are associated with neurodegenerative disease. Here, the authors identify in four families with hereditary spastic paraplegia biallelic mutations in RNF170 that associate with increased basal levels of IP3 receptors. |
| Databáze: | OpenAIRE |
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