CHRNA1 promotes the pathogenesis of primary focal hyperhidrosis
Introduction
Hyperhidrosis refers to excessive sweating in local, regional or the entire body, that can be caused by neurological, infectious, endocrine or pharmacological factors, as well as unknown causes therefore considered idiopathic in some cases (McConaghy and Fosselman, 2018). Primary focal hyperhidrosis (PFH) refers to local or regional hyperhidrosis and is distinguished by sweating in one or more sites including the hands, axillae, feet, forehand, or face, in addition to the crown or inguinal region (Smith and Pariser, 2018). PFH can be exacerbated by factors including stress, heat, gustatory and olfactory stimuli. PFH severely affects quality of life and work efficiencies and may even lead to serious psychological disorders if left untreated for a long period of time. It has been reported about 1.4% of the US population suffer from PFH (Lin et al., 2020). Thus far, treatments for PFH are limited to symptom alleviation, and precision medicine targeting molecular mechanisms driving PFH pathogenesis is limited. It is imperative to develop molecular targets for PFH treatment and elucidate their mechanisms of action.
An important pathological cause of PFH is the dysfunction of the autonomous sympathetic nervous system. Previous studies have shown that PFH is associated with up-regulation of acetylcholine receptor subunits, choline acetyltransferase and vasoactive intestinal peptide in the thoracic sympathetic ganglia (de Moura et al., 2013). A PFH-related gene on chromosome 2q31.1 has been identified through exome sequencing and genome-wide single nucleotide polymorphism chain scan analysis in a PPH-001 family of patients with familial inheritance (Chen et al., 2015). In combination with the Mapviewer database analysis of National Center for Biotechnology Information (NCBI), 30 genes with clearly defined functions have been identified as potential targets. Among them, cholinergic receptor nicotinic alpha 1 subunit (CHRNA1), which regulates the binding and gating of acetylcholine neurotransmitters, stood out due to its role in the sympathetic nervous system (Heckmann et al., 1996). Previously, dysregulated CHRNA1 levels were found to be associated with multiple neuromuscular disorders, such as congenital myasthenic syndrome (Abath Neto et al., 2017), myasthenia gravis (Li et al., 2017) and multiple pterygium syndrome (Vogt et al., 2008). More importantly, the CHRNA1 gene expression has been found to be significantly higher in the thoracic sympathetic ganglia of patients with hand sweating than normal subjects (Hurst et al., 2013). Acetylcholine blockers have been used to treat patients with PFH (Haider and Solish, 2005), and the enhanced expression of CHRNA1 gene may be one of the mechanisms underlying excessive sweat secretion.
Herein, we set out to elucidate the role of CHRNA1 in PFH by testing whether CHRNA1 was up-regulated in sweat gland tissues of PFH patients, and hyperhidrosis mice. The therapeutic potential of CHRNA1 silencing using small-interfering RNA (siRNA) was assessed in mice to evaluate whether this treatment alleviated PFH symptoms and reduced the level of PFH biomarker molecules. We showed that CHRNA1 up-regulation was a potential biomarker of PFH and down-regulating CHRNA1 was effective in alleviating the symptoms of PFH through inactivating the sympathetic system. Our study for the first time reports a link between the up-regulated CHRNA1 and PFH and could shed light on the potential of CHRNA1 as a therapeutic target in treating PFH.
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Patients
A total of 36 PFH patients in the First Affiliated Hospital of Fujian Medical University were admitted to the study. 18 PFH patients received single-hole operation at the axillary region in the hospital. Sweat gland tissues were collected with full layer skin (2 mm width and 5 mm length) at the right axillary incision. 18 patients had no palmar, axillary hyperhidrosis and family history, and no history of axillary osmidrosis as the control group. The same part of the right axillary incision was
Up-regulation of CHRNA1 in the sweat glands of PFH patients and hyperhidrosis mice
To assess the role of CHRNA1 in the pathogenesis of PFH, CHRNA1 expression levels in normal skin (harvested from the upper arm) and abnormal skin (harvested from the armpit) of 18 patients with PFH (Fig. 1A–B) and hyperhidrosis mice (Fig. 1C–D) were analyzed using Western blots and qRT-PCR. These analyses indicated that CHRNA1 was up-regulated in both protein and mRNA levels in both PFH patients and hyperhidrosis mice (p < 0.01). Thus, these data suggest that CHRNA1 is associated with
Discussion
Hyperhidrosis is caused by over activation of eccrine sweat glands mostly located in the soles, palms, forehead and axillae. Thus far, there is no evidence for histopathological changes in the eccrine sweat glands of hyperhidrosis patients (Griffen, 2018), and the dysfunction of the sympathetic nervous system is thought to majorly contribute to the pathogenesis of hyperhidrosis. For example, a recent study on the role of nitric oxide (NO) in the pathophysiology of PFH unveiled that PFH patients
Abbreviations
- CHRNA1
cholinergic receptor nicotinic alpha 1 subunit
- PFH
primary focal hyperhidrosis
- qRT-PCR
quantitative real-time PCR
- siRNA
small-interfering RNA
- AQP5
Aquaporin 5
- CACNA1C
Calcium Voltage-Gated Channel Subunit Alpha1 C
- BDNF
brain-derived neurotrophic factor
- NRG-1
Neuregulin 1
- NCBI
National Center for Biotechnology Information
Funding
This study was supported by Natural Science Foundation of China (Grant 81701241), Scientific and Joint Funds for the Innovation of Science and Technology, Fujian Province (Grant 2019Y9119), and Medical Innovation Project of Fujian Province (Grant 2020CXA037).
Declaration of competing interest
All authors declare that they have no conflict of interest.
Acknowledgments
None.
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These authors contributed equally to this work.