In:
Nature Communications, Springer Science and Business Media LLC, Vol. 10, No. 1 ( 2019-10-21)
Abstract:
Alterations of Ca 2+ homeostasis have been implicated in a wide range of neurodegenerative diseases. Ca 2+ 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.
Type of Medium:
Online Resource
ISSN:
2041-1723
DOI:
10.1038/s41467-019-12620-9
Language:
English
Publisher:
Springer Science and Business Media LLC
Publication Date:
2019
detail.hit.zdb_id:
2553671-0
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