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Novel heterozygous mutation in alpha-2-macroglobulin (A2M) suppressing the binding of amyloid-β (Aβ)
Guozhen Qiu1, Liming Cao2, Yong-Jun Chen3
1Cognitive Impairment Ward of Neurology Department, The Third Affiliated Hospital of Shenzhen University, Shenzhen, China.
Introduction:
Many studies have suggested that the alpha-2-macroglobulin (A2M) gene may be involved in the pathogenesis of Alzheimer's disease (AD). A2M encoded by the A2M gene can specifically bind to the β-amyloid peptide and prevent fiber formation.
Methods:
The patient in this study had progressive memory loss at the age of 60 years and underwent a series of neuropsychological tests, cranial magnetic resonance imaging (MRI), cerebrospinal fluid (CSF) biomarker analysis, and whole-exome sequencing (WES) to evaluate possible mutations. We used in silico tools and three-dimensional (3D) protein structure prediction to analyze the pathogenicity of the mutation and used a co-immunoprecipitation experiment to study the effect of mutations on amyloid-β (Aβ) binding.
Results:
Based on neuropsychological tests, cranial MRI, and CSF biomarker analysis, the patient was diagnosed with AD. WES showed that there was a missense mutation in A2M (c.1229A>C, p.N410T). Bioinformatics analysis showed that this mutation was pathogenic. Moreover, 3D protein structure analysis showed that the A2M Asn410 residue was an N-glycosylation site, which was necessary for A2M activation to bind to Aβ. Missense mutations led to the loss of glycosylation at this site, which suppressed the binding of Aβ. The functional experiment also confirmed the prediction: the interaction between A2M and Aβ from the patient's plasma was weakened.
Conclusions:
Our results demonstrate that this novel A2M p.N410T mutation may have a pathogenic role in AD, by altering the binding interactions between A2M and Aβ.
Insights
A novel mutation in the alpha-2-macroglobulin (A2M) gene, p.N410T, was identified in an Alzheimer's disease patient. This A2M mutation impairs binding to amyloid-beta, suggesting a role in Alzheimer's pathogenesis.
Area of Science:
- Neuroscience
- Genetics
- Biochemistry
Background:
- Alzheimer's disease (AD) is a progressive neurodegenerative disorder.
- Alpha-2-macroglobulin (A2M) is implicated in AD pathogenesis due to its ability to bind amyloid-beta (Aβ) and inhibit its aggregation.
- Genetic variations in A2M may influence AD risk and progression.
Purpose of the Study:
- To investigate the role of a novel A2M mutation in a patient diagnosed with Alzheimer's disease.
- To analyze the functional impact of the identified A2M mutation on Aβ binding.
- To explore the pathogenic mechanism linking A2M dysfunction to AD.
Main Methods:
- Whole-exome sequencing (WES) to identify genetic mutations.
- In silico tools and 3D protein structure prediction to assess mutation pathogenicity.
- Co-immunoprecipitation assays to evaluate A2M-Aβ binding interactions.
Main Results:
- A patient with progressive memory loss was diagnosed with AD.
- WES revealed a pathogenic missense mutation in A2M (c.1229A>C, p.N410T).
- The p.N410T mutation disrupts an N-glycosylation site crucial for A2M activation, weakening Aβ binding.
Conclusions:
- The novel A2M p.N410T mutation is associated with Alzheimer's disease.
- This mutation contributes to AD pathogenesis by impairing A2M's ability to bind Aβ.
- Understanding A2M's role in AD provides insights into potential therapeutic targets.
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