Protein S-palmitoylation, the covalent lipid modification of the side chain of Cys residues with the 16‑carbon fatty acid palmitate, is the most common acylation, and it enhances the membrane stability of ion channels. This post-translational modification (PTM) determines a functional mechanism of ion channel life cycle from maturation and membrane trafficking to localization. Especially, neurodevelopment is regulated by balancing the level of synaptic protein palmitoylation/depalmitoylation. Recently, we revealed the pathological role of the transient receptor potential canonical type 5 (TRPC5) channel in striatal neuronal loss during Huntington's disease (HD), which is abnormally activated by oxidative stress. Here, we report a mechanism of TRPC5 palmitoylation at a conserved cysteine residue, that is critical for intrinsic channel activity. Furthermore, we identified the therapeutic effect of TRPC5 depalmitoylation by enhancing the TRPC5 membrane instability on HD striatal cells in order to lower TRPC5 toxicity. Collectively, these findings suggest that controlling S-palmitoylation of the TRPC5 channel as a potential risk factor can modulate TRPC5 channel expression and activity, providing new insights into a therapeutic strategy for neurodegenerative diseases.

中文翻译：

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去棕榈酸酯化诱导的TRPC5通道不稳定性可保护纹状体神经元免受亨廷顿氏病的氧化应激。

最常见的酰化是蛋白质S-棕榈酰化（Cys残基的侧链与16-碳脂肪酸棕榈酸酯共价修饰脂质），是最常见的酰化反应，可增强离子通道的膜稳定性。这种翻译后修饰（PTM）确定了离子通道生命周期从成熟和膜运输到定位的功能机制。特别地，通过平衡突触蛋白棕榈酰化/去棕榈酰化的水平来调节神经发育。最近，我们揭示了在亨廷顿氏病（HD）期间纹状体神经元丢失（由氧化应激异常激活）中的瞬时受体电位5型规范（TRPC5）通道的病理学作用。在这里，我们报告保守的半胱氨酸残基上的TRPC5棕榈酰化的机制，这对于固有通道活性至关重要。此外，我们通过增强HD纹状体细胞上的TRPC5膜不稳定性来降低TRPC5毒性，从而确定了TRPC5去棕榈酸酯化的治疗效果。总体而言，这些发现表明，控制TRPC5通道的S-棕榈酰化作为潜在的危险因素可以调节TRPC5通道的表达和活性，为神经退行性疾病的治疗策略提供新的见解。