1. TRPC5 channel instability induced by depalmitoylation protects striatal neurons against oxidative stress in Huntington's disease
- Author
-
Byeongseok Jeong, Jae Yeoul Jun, Juyeon Ko, Hyung Joon Park, Insuk So, Seok Choi, Seo Hwa Choi, Misun Kwak, and Chansik Hong
- Subjects
0301 basic medicine ,Lipoylation ,Amino Acid Motifs ,Palmitates ,Golgi Apparatus ,Apoptosis ,Mice, Transgenic ,medicine.disease_cause ,TRPC5 ,Mice ,03 medical and health sciences ,Transient receptor potential channel ,0302 clinical medicine ,Palmitoylation ,Huntington's disease ,medicine ,Animals ,Humans ,Antineoplastic Agents, Alkylating ,Molecular Biology ,Ion channel ,TRPC ,TRPC Cation Channels ,Neurons ,Huntingtin Protein ,Protein Stability ,Chemistry ,Cell Biology ,medicine.disease ,Carmustine ,Cell biology ,Oxidative Stress ,Protein Subunits ,HEK293 Cells ,Huntington Disease ,030104 developmental biology ,Mutagenesis, Site-Directed ,Lipid modification ,030217 neurology & neurosurgery ,Oxidative stress - Abstract
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.
- Published
- 2020