近日，美国斯克利普斯研究所Ardem Patapoutian及其小组发现，感觉神经元的过度机械传导会导致关节挛缩。这一研究成果于2023年1月13日发表在国际学术期刊《科学》上。

研究人员表示，远端关节挛缩症（DA）是一组以先天性关节挛缩为特征的罕见疾病。大多数DA突变是在肌肉和关节相关的基因中，解剖学上的缺陷起源于肌肉骨骼系统的细胞自主性。然而，PIEZO2是体感中的一个主要机械传感器，其功能增益突变通过未知的机制引起DA亚型5（DA5）。

研究人员发现，在主要支配肌轴和肌腱的本体感觉神经元中表达功能增益的PIEZO2突变，足以诱发小鼠DA5样的表型。过度活跃的PIEZO2在出生后的发育过程中通过增加周围神经系统内的活动导致解剖学缺陷。此外，肉毒杆菌毒素（Botox）和一种调节PIEZO2活性的膳食脂肪酸能减少DA5样缺陷。这揭示了体感神经元的作用。这些神经元内过度的机械感觉破坏了肌肉骨骼的发育。

附：英文原文

Title: Excessive mechanotransduction in sensory neurons causes joint contractures

Author: Shang Ma, Adrienne E. Dubin, Luis O. Romero, Meaghan Loud, Alexandra Salazar, Sarah Chu, Nikola Klier, Sameer Masri, Yunxiao Zhang, Yu Wang, Alex T. Chesler, Katherine A. Wilkinson, Valeria Vásquez, Kara L. Marshall, Ardem Patapoutian

Issue&Volume: 2023-01-13

Abstract: Distal arthrogryposis (DA) is a collection of rare disorders that are characterized by congenital joint contractures. Most DA mutations are in muscle- and joint-related genes, and the anatomical defects originate cell-autonomously within the musculoskeletal system. However, gain-of-function mutations in PIEZO2, a principal mechanosensor in somatosensation, cause DA subtype 5 (DA5) through unknown mechanisms. We show that expression of a gain-of-function PIEZO2 mutation in proprioceptive sensory neurons that mainly innervate muscle spindles and tendons is sufficient to induce DA5-like phenotypes in mice. Overactive PIEZO2 causes anatomical defects through increased activity within the peripheral nervous system during postnatal development. Furthermore, botulinum toxin (Botox) and a dietary fatty acid that modulates PIEZO2 activity reduce DA5-like deficits. This reveals a role for somatosensory neurons: Excessive mechanosensation within these neurons disrupts musculoskeletal development.

DOI: add3598

Source: https://www.science.org/doi/10.1126/science.add3598