期刊
EMBO JOURNAL
卷 41, 期 2, 页码 -出版社
WILEY
DOI: 10.15252/embj.2020105531
关键词
actin cytoskeleton; cell adhesion; integrins; intellectual disability; protein disulfide isomerase
资金
- FONDECYT [1191538, 1200459, 1161524, 1140549, 11180825, 11140430]
- DICYT [021843RS, 021843MM, 021943MM_POSTDOC]
- CONICYT [PIA ACT 192015]
- FONDEQUIP [EQM130051]
- Nucleus Physics of Active Matter
- FONDAP [15150012]
- Millennium Institute [P09-015-F]
- European Commission [734749]
- URF-QAU Pakistan
- AOF [318182]
- Biocenter Oulu
- Bogazici University Research Fund [7695]
- Muscular Dystrophy Association [575897]
- ALS Association [19-IIA-456]
- FONDEF [ID16I10223, ID11E1007]
- Michael J Fox Foundation for Parkinson's Research-Target Validation grant [9277]
- US Office of Naval Research-Global [N62909-16-1-2003]
- US Air Force Office of Scientific Research [FA9550-16-1-0384]
- Department of Defense [W81XWH2110960]
A study identified a PDIA3 gene mutation associated with syndromic intellectual disability, leading to developmental defects and abnormal neuronal function. Experimental findings in zebrafish and mice demonstrated the detrimental effects of this mutation, shedding light on the impact of neuronal proteostasis on nervous system function.
Recessive gene mutations underlie many developmental disorders and often lead to disabling neurological problems. Here, we report identification of a homozygous c.170G>A (p.Cys57Tyr or C57Y) mutation in the gene coding for protein disulfide isomerase A3 (PDIA3, also known as ERp57), an enzyme that catalyzes formation of disulfide bonds in the endoplasmic reticulum, to be associated with syndromic intellectual disability. Experiments in zebrafish embryos show that PDIA3(C57Y) expression is pathogenic and causes developmental defects such as axonal disorganization as well as skeletal abnormalities. Expression of PDIA3(C57Y) in the mouse hippocampus results in impaired synaptic plasticity and memory consolidation. Proteomic and functional analyses reveal that PDIA3(C57Y) expression leads to dysregulation of cell adhesion and actin cytoskeleton dynamics, associated with altered integrin biogenesis and reduced neuritogenesis. Biochemical studies show that PDIA3(C57Y) has decreased catalytic activity and forms disulfide-crosslinked aggregates that abnormally interact with chaperones in the endoplasmic reticulum. Thus, rare disease gene variant can provide insight into how perturbations of neuronal proteostasis can affect the function of the nervous system.
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