ICA1 affects APP processing through the PICK1-PKCα signaling pathway.
Liangye Ji1, ZiJun Meng1, Xiangjun Dong1
1Department of Pediatric Research Institute Children's Hospital of Chongqing Medical University, National Clinical Research Center for Child Health and Disorders, Ministry of Education Key Laboratory of Child Development and Disorders, China International Science and Technology Cooperation base of Child development and Critical Disorders, Chongqing Key Laboratory of Child Neurodevelopment and Cognitive Disorders, Children's Hospital of Chongqing Medical University, Chongqing, China.
CNS Neuroscience & Therapeutics
|June 17, 2024
Summary
Islet cell autoantigen 1 (ICA1) expression is reduced in Alzheimer's disease (AD). ICA1 influences amyloid precursor protein processing, suggesting it as a potential therapeutic target for AD.
Area of Science:
- Neuroscience
- Molecular Biology
- Immunology
Background:
- Islet cell autoantigen 1 (ICA1) is implicated in autoimmune disorders and may influence synaptic plasticity.
- Reduced ICA1 expression is observed in Alzheimer's disease (AD) patients, but its specific role in AD pathogenesis is not fully understood.
Purpose of the Study:
- To investigate the role of ICA1 in Alzheimer's disease (AD).
- To determine the effect of ICA1 on amyloid precursor protein (APP) processing and related signaling pathways.
Main Methods:
- Analysis of ICA1 expression in AD patient brains and an AD mouse model.
- Assessment of ICA1's impact on APP, ADAM10, and ADAM17 expression.
- Transcriptome sequencing to identify regulated pathways.
- Investigation of ICA1's effect on PKCα protein levels and phosphorylation.
Main Results:
- ICA1 expression was found to be decreased in the brains of AD patients and an AD mouse model.
- ICA1 overexpression led to increased expression of amyloid precursor protein (APP), ADAM10, and ADAM17, without altering protein half-life or mRNA levels.
- Transcriptome analysis indicated that ICA1 regulates the G protein-coupled receptor signaling pathway.
- Overexpression of ICA1 resulted in elevated PKCα protein levels and phosphorylation.
Conclusions:
- ICA1 plays a role in modulating APP processing, shifting it towards non-amyloidogenic pathways.
- Regulation of the PICK1-PKCα signaling pathway by ICA1 is a key mechanism.
- ICA1 represents a potential novel therapeutic target for Alzheimer's disease (AD).
Related Concept Videos
01:19Interactions Between Signaling Pathways
6.3K
Signaling cascades usually lack linearity. Multiple pathways interact and regulate one another, allowing cells to integrate and respond to diverse environmental stimuli.
Convergence and divergence, and cross-talk between signaling pathways
Two distinct signaling pathways can converge on a single functional unit, which may either be a single protein or a complex of proteins. The response is either functionally distinct or synergistic between the two pathways but different from the response...
Convergence and divergence, and cross-talk between signaling pathways
Two distinct signaling pathways can converge on a single functional unit, which may either be a single protein or a complex of proteins. The response is either functionally distinct or synergistic between the two pathways but different from the response...
6.3K
01:25cAMP-dependent Protein Kinase Pathways
6.3K
Cyclic Adenosine Monophosphate (cAMP) is an essential second messenger that activates protein kinase A (PKA) and regulates various biological processes. A single epinephrine molecule binds to GPCR and activates several heterotrimeric G proteins, each stimulating multiple adenylyl cyclase, amplifying the signal, and synthesizing large numbers of cAMP molecules. Small changes in cAMP concentration affect PKA activity. The binding of four cAMP molecules induces a conformational change in PKA,...
6.3K
01:24Intracellular Signaling Cascades
46.6K
Once a ligand binds to a receptor, the signal is transmitted through the membrane and into the cytoplasm. The continuation of a signal in this manner is called signal transduction. Signal transduction only occurs with cell-surface receptors, which cannot interact with most components of the cell, such as DNA. Only internal receptors can interact directly with DNA in the nucleus to initiate protein synthesis. When a ligand binds to its receptor, conformational changes occur that affect the...
46.6K
01:11IP3/DAG Signaling Pathway
12.0K
Membrane lipids such as phosphatidylinositol (PI) are precursors for several membrane-bound and soluble second messengers. Specific kinases phosphorylate PI and produce phosphorylated inositol phospholipids. One such inositol phospholipids are the phosphatidylinositol-4,5 bisphosphate [PI(4,5)P2], present in the inner half of the lipid bilayer. Upon ligand binding, GPCR stimulates Gq proteins to turn on phospholipase Cꞵ. Activated phospholipase Cꞵ cleaves PI(4,5)P2 and...
12.0K
01:16Calmodulin-dependent Signaling
5.1K
Calmodulin (CaM) is a calcium-binding protein in eukaryotes that controls various calcium-regulated cellular processes. It has four calcium-binding sites that bind calcium to form the calcium-calmodulin ( Ca2+-CaM) complex. GPCR stimulation increases the calcium levels in the cells that bind to CaM and induces a conformational change.
The Ca2+-CaM complex does not have enzymatic activity by itself. Instead, the complex binds downstream target proteins, including membrane proteins or enzymes,...
The Ca2+-CaM complex does not have enzymatic activity by itself. Instead, the complex binds downstream target proteins, including membrane proteins or enzymes,...
5.1K
01:22Amplifying Signals via Enzymatic Cascade
8.5K
When a ligand binds to a cell-surface receptor, the receptor's intracellular domain changes shape, which may either activate its enzyme function or allow its binding to other molecules. The initial signal is amplified by most signal transduction pathways. This means that a single ligand molecule can activate multiple molecules of a downstream target. Proteins that relay a signal are most commonly phosphorylated at one or more sites, activating or inactivating the protein. Kinases catalyze...
8.5K