التفاصيل البيبلوغرافية
| العنوان: |
Aberrant palmitoylation caused by a ZDHHC21 mutation contributes to pathophysiology of Alzheimer’s disease |
| المؤلفون: |
Li, Wenwen, Pang, Yana, Wang, Yan, Mei, Fan, Guo, Mengmeng, Wei, Yiping, Li, Xinyue, Qin, Wei, Wang, Wei, Jia, Longfei, Jia, Jianping |
| المساهمون: |
National Natural Science Foundation of China, Beijing Municipal Science and Technology Commission, National major R&D projects of China-Scientific technological innovation 2030, National Key Scientific Instrument and Equipment Development Project |
| المصدر: |
BMC Medicine ; volume 21, issue 1 ; ISSN 1741-7015 |
| بيانات النشر: |
Springer Science and Business Media LLC |
| سنة النشر: |
2023 |
| مصطلحات موضوعية: |
General Medicine |
| الوصف: |
Background The identification of pathogenic mutations in Alzheimer’s disease (AD) causal genes led to a better understanding of the pathobiology of AD. Familial Alzheimer’s disease (FAD) is known to be associated with mutations in the APP, PSEN1, and PSEN2 genes involved in Aβ production; however, these genetic defects occur in only about 10–20% of FAD cases, and more genes and new mechanism causing FAD remain largely obscure. Methods We performed exome sequencing on family members with a FAD pedigree and identified gene variant ZDHHC21 p.T209S. A ZDHHC21 T209S/T209S knock-in mouse model was then generated using CRISPR/Cas9. The Morris water navigation task was then used to examine spatial learning and memory. The involvement of aberrant palmitoylation of FYN tyrosine kinase and APP in AD pathology was evaluated using biochemical methods and immunostaining. Aβ and tau pathophysiology was evaluated using ELISA, biochemical methods, and immunostaining. Field recordings of synaptic long-term potentiation were obtained to examine synaptic plasticity. The density of synapses and dendritic branches was quantified using electron microscopy and Golgi staining. Results We identified a variant (c.999A > T, p.T209S) of ZDHHC21 gene in a Han Chinese family. The proband presented marked cognitive impairment at 55 years of age (Mini-Mental State Examination score = 5, Clinical Dementia Rating = 3). Considerable Aβ retention was observed in the bilateral frontal, parietal, and lateral temporal cortices. The novel heterozygous missense mutation (p.T209S) was detected in all family members with AD and was not present in those unaffected, indicating cosegregation. ZDHHC21 T209S/T209S mice exhibited cognitive impairment and synaptic dysfunction, suggesting the strong pathogenicity of the mutation. The ZDHHC21 p.T209S mutation significantly enhanced FYN palmitoylation, causing overactivation of NMDAR2B, inducing increased neuronal sensitivity to excitotoxicity leading to further synaptic dysfunction and neuronal loss. ... |
| نوع الوثيقة: |
article in journal/newspaper |
| اللغة: |
English |
| DOI: |
10.1186/s12916-023-02930-7 |
| DOI: |
10.1186/s12916-023-02930-7.pdf |
| DOI: |
10.1186/s12916-023-02930-7/fulltext.html |
| الإتاحة: |
https://doi.org/10.1186/s12916-023-02930-7Test |
| حقوق: |
https://creativecommons.org/licenses/by/4.0Test ; https://creativecommons.org/licenses/by/4.0Test |
| رقم الانضمام: |
edsbas.8B8A66E3 |
| قاعدة البيانات: |
BASE |
