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

• 成果类型: Article
• 署名作者: Wang, Na; Zhu, Biqing; Allnutt, Mary Alice; Grijalva, Rosalie M.; Zhao, Hongyu; Chandra, Sreeganga S.
• 署名单位: Yale University; Yale University; Yale University; Yale University; Yale University
• 刊物名称: PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
• ISSN/ISSBN: 0027-15161
• DOI: 10.1073/pnas.2320064121
• 发表日期: 2024-06-11
• 关键词: neuronal ceroid-lipofuscinosis; csp-alpha; cell-adhesion; neuroligin; neurexins; mutations; chaperone; dnajc5; neurodegeneration; identification

摘要

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 alpha (CSP alpha ), 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 singlenucleus transcriptomics on the cortex of young CSP alpha 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 CSP alpha KO brain. Significantly, all neuronal classes in CSP alpha 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 CSP alpha 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 CSP alpha KO mice to preserve synapse maintenance. Together, this study provides a rich dataset of transcriptional changes in the CSP alpha KO cortex and reveals insights into synapse maintenance and neurodegeneration.