Decoding transcriptomic signatures of cysteine string protein alpha–mediated synapse maintenance

Author:

Wang Na12ORCID,Zhu Biqing34ORCID,Allnutt Mary Alice125,Grijalva Rosalie M.25,Zhao Hongyu34ORCID,Chandra Sreeganga S.12ORCID

Affiliation:

1. Department of Neurology, Yale University, New Haven, CT 06510

2. Department of Neuroscience, Yale University, New Haven, CT 06510

3. Program of Computational Biology and Bioinformatics, Yale University, New Haven, CT 06510

4. Department of Biostatistics, Yale School of Public Health, New Haven, CT 06510

5. Interdepartmental Neuroscience Program, Yale University, New Haven, CT 06510

Abstract

Synapse maintenance is essential for generating functional circuitry, and decrement in this process is a hallmark of neurodegenerative disease. Yet, little is known about synapse maintenance in vivo. Cysteine string protein α (CSPα), encoded by the Dnajc5 gene, is a synaptic vesicle chaperone that is necessary for synapse maintenance and linked to neurodegeneration. To investigate the transcriptional changes associated with synapse maintenance, we performed single-nucleus transcriptomics on the cortex of young CSPα knockout (KO) mice and littermate controls. Through differential expression and gene ontology analysis, we observed that both neurons and glial cells exhibit unique signatures in the CSPα KO brain. Significantly, all neuronal classes in CSPα KO brains show strong signatures of repression in synaptic pathways, while up-regulating autophagy-related genes. Through visualization of synapses and autophagosomes by electron microscopy, we confirmed these alterations especially in inhibitory synapses. Glial responses varied by cell type, with microglia exhibiting activation. By imputing cell–cell interactions, we found that neuron–glia interactions were specifically increased in CSPα KO mice. This was mediated by synaptogenic adhesion molecules, with the classical Neurexin1–Neuroligin 1 pair being the most prominent, suggesting that communication of glial cells with neurons is strengthened in CSPα KO mice to preserve synapse maintenance. Together, this study provides a rich dataset of transcriptional changes in the CSPα KO cortex and reveals insights into synapse maintenance and neurodegeneration.

Funder

HHS | NIH | National Institute of Neurological Disorders and Stroke

Nina Compagnon Hirshfield Parkinson's Disease Research Fund

Publisher

Proceedings of the National Academy of Sciences

同舟云学术

1.学者识别学者识别

2.学术分析学术分析

3.人才评估人才评估

"同舟云学术"是以全球学者为主线,采集、加工和组织学术论文而形成的新型学术文献查询和分析系统,可以对全球学者进行文献检索和人才价值评估。用户可以通过关注某些学科领域的顶尖人物而持续追踪该领域的学科进展和研究前沿。经过近期的数据扩容,当前同舟云学术共收录了国内外主流学术期刊6万余种,收集的期刊论文及会议论文总量共计约1.5亿篇,并以每天添加12000余篇中外论文的速度递增。我们也可以为用户提供个性化、定制化的学者数据。欢迎来电咨询!咨询电话:010-8811{复制后删除}0370

www.globalauthorid.com

TOP

Copyright © 2019-2024 北京同舟云网络信息技术有限公司
京公网安备11010802033243号  京ICP备18003416号-3