Song, X.-L. | Search bioRxiv

bioRxiv2024

Multi-omics Identify Serotonin Transporter as a Promising Therapeutic Target for Essential Tremor

Essential tremor (ET) stands as one of the most prevalent cerebellar movement disorders. However, effective treatment remains elusive, largely due to a limited understanding of its molecular pathology. Harmaline-induced tremor in mouse is a well-established animal model for ET, while with enigmatic mechanism. The aim of this study was to get insight into the molecular intricacies underlying cerebellar dysfunction in harmaline-induced tremor. Combining LC-MS/MS and RNA-Seq analysis, we delved into the variation of the cerebellum between harmaline-induced tremor and the control ones. This comprehensive investigation revealed a profile of this mouse model from mRNA and protein level, highlighting 5194 correlated coding molecules, with 19 proving to be significant. Further KEGG enrichment analysis identified cerebellar serotonin transporter (SERT) as the key molecule in harmaline-induced tremor. The implications of this transcriptomic and proteomic exploration underscore the potential therapeutic value of targeting SERT as a novel treatment approach for ET. In general, our study unveils crucial insights that could pave the way for molecular target identification and effective therapeutic interventions for ET.

neuroscience↗

bioRxiv2022

Phosphatidylserine controls synaptic targeting and membrane stability of ASIC1a

Phospholipid-protein interaction is highly specialized at the membranous nanodomains and critical for membrane receptor signaling. Calcium-permeable acid-sensing ion channel isoform 1a (ASIC1a) is a major neuronal proton sensor that contributes to synaptic plasticity. The functional outcome of ASIC1a is dependent on its surface targeting in synaptic subdomains; however, the lipid environment for ASIC1a and its role in channel targeting remain poorly understood. Here, we report that anionic phosphatidylserine (PS) is enriched in dendritic spines during neurodevelopment and it directly binds to ASIC1a through an electrostatic interaction with a di-arginine motif at ASIC1a C-terminus. PS regulates the membrane targeting and function of ASIC1a, which are both strongly suppressed by inhibition of PS synthesis. In cortical neuron dendrites, both PS and ASIC1a are predominately localized to peri-synaptic sites of spine heads, surrounding instead of overlapping with postsynaptic markers, PSD-95 and GluN1. Uncoupling the interaction between PS and ASIC1a by changing the charges to neutral or acidic at the di-arginine PS-binding motif, or applying a membrane penetrating competing peptide, caused mistargeting of ASIC1a at the synaptic sites, an overall increase in internalization and/or cytoplasmic accumulation of ASIC1a, and a decrease in its channel function. Together, our results provide novel insights on lipid microenvironment that governs ASIC1a expression and function at the membrane surface, especially peri-synaptic regions of dendritic spines, through an electrostatic interaction with anionic phospholipids.

neuroscience↗