Elevated vesicular Zn2+ in dorsal root ganglion neurons expressing the transporter TMEM163 causes age-associated itchy skin in mice
The prevalent itching condition associated with aging, historically referred to as senile pruritus, diminishes quality of life. Despite its impact, effective treatments remain elusive, largely due to an incomplete understanding of its pathological cause. In this study, we reveal a subset of dorsal root ganglion neurons enriched with Zn2+ that express the vesicular Zn2+ transporter TMEM163. These neurons form direct synapses with and modulate the activity of spinal NPY+ inhibitory interneurons. In aged mice, both the expression of TMEM163 and the concentration of vesicular Zn2+ within the central terminals of TMEM163+ primary afferents show marked elevation. Importantly, the excessive release of vesicular Zn2+ significantly dampens the activity of NPY+ neurons, triggering the disinhibition of itch-transmitting neural circuits and resulting in chronic itch. Intriguingly, chelating Zn2+ within the spinal dorsal horn effectively relieves itch in aged mice. Our study thus unveils a novel molecular mechanism underlying senile pruritus.
Authors
- Xicheng Gu (ORCID: https://orcid.org/0009-0009-9787-6984)
- Xinghuan Wang (ORCID: https://orcid.org/0000-0003-3497-0024)
- Liang Chen (ORCID: https://orcid.org/0000-0002-7507-3947)
- Bin Zhou (ORCID: https://orcid.org/0000-0002-1535-6283)
- Qianhui Qu (ORCID: https://orcid.org/0000-0002-5753-2599)
- Qingjian Han (ORCID: https://orcid.org/0000-0001-6641-7499)
- Haili Pan (ORCID: https://orcid.org/0000-0003-3859-0758)
- Shuai Liu (ORCID: https://orcid.org/0000-0003-0792-4743)
- Jianwei Chen (ORCID: https://orcid.org/0000-0002-5749-0085)
- Changlin Li (ORCID: https://orcid.org/0000-0001-5872-6443)
- Ye Gong
- Huan Yang (ORCID: https://orcid.org/0000-0001-8625-6223)
- Fang Tong
- Xin Zhang (ORCID: https://orcid.org/0000-0003-0047-3134)
- Chen Zhang (ORCID: https://orcid.org/0000-0003-0988-8723)
Institutions
- Fudan University (CN)
- Guangdong Polytechnic of Science and Technology (CN)
- Shanghai Stomatological Hospital (CN)
- First Affiliated Hospital of Jiangxi Medical College (CN)
- Jiangxi Provincial People's Hospital (CN)
- Wuxi People's Hospital (CN)
- State Key Laboratory of Medical Neurobiology
- Nanjing Medical University (CN)
Publication Details
- Journal
- PLoS Biology
- Published
- 2024-11-27
- DOI
- https://doi.org/10.1371/journal.pbio.3002888
- Citations
- 4
- Primary Topic
- Dermatology and Skin Diseases
- Type
- article
- Field-Weighted Citation Impact
- 2.14
Funders
- Natural Science Foundation of Shanghai
- National Natural Science Foundation of China