PIGK defects induce apoptosis in Purkinje cells and acceleration of neuroectodermal differentiation

Biallelic mutations in PIGK cause GPI biosynthesis defect 22 (GPIBD22), characterized with developmental delay, hypotonia, and cerebellar atrophy. The understanding of the underlying causes is limited due to the lack of suitable disease models. To address this gap, we generated a mouse model with PI...

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Bibliographic Details
Published in:Cell death & disease 2024-11, Vol.15 (11), p.808-11, Article 808
Main Authors: Chen, Siyi, You, Jiali, Zhou, Xiaowei, Li, Yan, Liu, Fang, Teng, Yanling, Teng, Hua, Li, Yunlong, Liang, Desheng, Li, Zhuo, Wu, Lingqian
Format: Article
Language:English
Subjects:
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Animal models
Animals
Antibodies
Apoptosis
Apoptosis - genetics
Ataxia
Atrophy
Biochemistry
Biomedical and Life Sciences
Cell Biology
Cell Culture
Cell Differentiation
Cerebellum
Humans
Immunology
Induced Pluripotent Stem Cells - metabolism
Inhibitory postsynaptic potentials
Life Sciences
Mice
Mice, Inbred C57BL
Mice, Knockout
Mutation
Neural stem cells
Neural Stem Cells - metabolism
Neural Stem Cells - pathology
Pluripotency
Progenitor cells
Protein folding
Purkinje cells
Purkinje Cells - metabolism
Purkinje Cells - pathology
Rosette formation
Unfolded Protein Response
Citations: Items that this one cites
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Summary:Biallelic mutations in PIGK cause GPI biosynthesis defect 22 (GPIBD22), characterized with developmental delay, hypotonia, and cerebellar atrophy. The understanding of the underlying causes is limited due to the lack of suitable disease models. To address this gap, we generated a mouse model with PIGK deficits, specifically in Purkinje cells (Pcp2-cko) and an induced pluripotent stem cell (iPSC) model using the c.87dupT mutant (KI) found in GPIBD22 patients. Pcp2-cko mice demonstrated cerebellar atrophy, ataxia and progressive Purkinje cells loss which were accompanied by increased apoptosis and neuroinflammation. Similarly, KI iPSCs exhibited increased apoptosis and accelerated neural rosette formation, indicating that PIGK defects could impact early neural differentiation that confirmed by the RNA-Seq results of neural progenitor cells (NPCs). The increased apoptosis and accelerated NPC differentiation in KI iPSCs are associated with excessive unfolded protein response (UPR) pathway activation, and can be rescued by UPR pathway inhibitor. Our study reveals potential pathogenic mechanism of GPIBD22 and providing new insights into the therapeutic strategy for GPIBD.
ISSN:2041-4889
2041-4889
DOI:10.1038/s41419-024-07201-8