Disruption of Intracellular Calcium Homeostasis Leads to ERLIN2-Linked Hereditary Spastic Paraplegia in Patient-Derived Stem Cell Models

Hereditary spastic paraplegia (HSP) is a category of neurodegenerative illnesses with significant clinical and genetic heterogeneity. Homozygous truncated variants of the ERLIN2 gene lead to HSP18 (MIM #611225). However, it is still unclear whether there is an autosomal dominant pathogenic pattern....

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Bibliographic Details
Published inHuman mutation Vol. 2023; pp. 1 - 14
Main Authors Zhu, Xintong, Tan, Xiaoyin, Wang, Junwen, Dai, Limeng, Li, Jia, Guan, Xingying, Wang, Ziyi, Zhang, Mao, Hu, Jun, Bai, Yun, Guo, Hong
Format Journal Article
LanguageEnglish
Published Hoboken Hindawi 16.06.2023
Hindawi Limited
Subjects
Apoptosis
Autosomal dominant inheritance
Calcium (intracellular)
Calcium (reticular)
Calcium homeostasis
Cell culture
Cell cycle
Cell proliferation
Endoplasmic reticulum
Genes
Hereditary spastic paraplegia
Homeostasis
Inositol 1,4,5-trisphosphate receptors
Intracellular
MAP kinase
Mass spectroscopy
Molecular modelling
Mutation
Neurons
Paralysis
Patients
Proteins
Signal transduction
Spasticity
Stem cells
Ubiquitin
Ubiquitin-protein ligase
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Summary:Hereditary spastic paraplegia (HSP) is a category of neurodegenerative illnesses with significant clinical and genetic heterogeneity. Homozygous truncated variants of the ERLIN2 gene lead to HSP18 (MIM #611225). However, it is still unclear whether there is an autosomal dominant pathogenic pattern. The specific molecular mechanism needs to be investigated. We generated patient-derived iPSC models to study the mechanism of ERLIN2 heterogeneous variants leading to HSP. We identified a heterozygous missense variant p.Val71Ala of ERLIN2 in an HSP family. Based on IP-mass spectrometry, we found that the ERLIN2 heterozygous missense variant protein recruited the ubiquitin E3 ligase RNF213 to degrade IP3R1. The degradation of IP3R1 leads to the reduction of intracellular free calcium, which triggered endoplasmic reticulum (ER) stress-mediated apoptosis. Calcium homeostasis imbalance inhibited the MAPK signaling pathway that contributed to decreased cell proliferation. In summary, these results suggest that the autosomal dominant inheritance of heterozygous missense variants in ERLIN2 is a novel pathogenic mode of HSP. Furthermore, the disruption of intracellular calcium homeostasis is the pathological mechanism.
ISSN:1098-1004
1059-7794
1098-1004
DOI:10.1155/2023/4834423