Leung, Y.-Y. | bioRxiv Science

bioRxiv2024

GABAAR-PPT1 palmitoylation homeostasis controls synaptic transmission and circuitry oscillation in CLN1 disease

CLN1 disease, also called infantile neuronal ceroid lipofuscinosis, is a fatal neurodegenerative disease caused by mutations in the CLN1 gene encoding palmitoyl protein thioesterase 1 (PPT1). To identify depalmitoylation substrate of PPT1 is crucial to understand CLN1 disease. In this study, we found that PPT1 depalmitoylates GABAAR 1 subunit at Cystein-260, while binding to Cystein-165 and -179. Mutations of PPT1 or its GABAAR 1 subunit binding site result in enhanced inhibitory synaptic transmission, strengthened and oscillation but disrupted phase coupling in CA1 region and impaired learning and memory in 1- to 2-months-old PPT1-deficient and Gabra1em1 mice. Our study highlights the critical role of PPT1 in maintaining GABAAR palmitoylation homeostasis and reveals a previously unknown molecular pathway in PPT1 induced diseases.

neuroscience↗

bioRxiv2023

Altered astrocytic and microglial homeostasis characterizes a decreased proinflammatory state in bipolar disorder

Multiple lines of evidence point to peripheral immune alterations in bipolar disorder (BD) although the activity of brain immune mechanisms remain largely unexplored. To identify the cell type-specific immune alterations in the BD brain, we performed a proteomic and single nuclear transcriptomic analysis of postmortem cingulate cortex samples from BD and control subjects. Our results showed that genes associated to the genetic risk for BD are enriched in microglia and astrocytes. Transcriptomic alterations in microglia point to a reduced proinflammatory phenotype, associated to reduced resistance to oxidative stress and apoptosis, which was confirmed with immunohistochemical quantification of IBA1 density. Astrocytes show transcriptomic evidence of an imbalance of multiple metabolic pathways, extracellular matrix composition and downregulated immune signalling. These alterations are associated to ADCY2 and NCAN, two GWAS genes upregulated in astrocytes. Finally, cell-cell communication analysis prioritized upregulated SPP1-CD44 signalling to astrocytes as a potential regulator of the transcriptomic alterations in BD. Our results indicate that microglia and astrocytes are characterized by downregulated immune responses associated to a dysfunction of core mechanisms via which these cells contribute to brain homeostasis.

neuroscience↗