Nagy Zsófia Flóra, Sonkodi Balázs, Pál Margit, Klivényi Péter, Széll Márta
Department of Medical Genetics, Albert Szent-Györgyi Medical School, University of Szeged, 6725 Szeged, Hungary.
Department of Health Sciences and Sport Medicine, Hungarian University of Sports Science, 1123 Budapest, Hungary.
Biomedicines. 2023 Mar 17;11(3):933. doi: 10.3390/biomedicines11030933.
Amyotrophic lateral sclerosis (ALS) is a lethal multisystem neurodegenerative disease associated with progressive loss of motor neurons, leading to death. Not only is the clinical picture of ALS heterogenous, but also the pain sensation due to different types of pain involvement. ALS used to be considered a painless disease, but research has been emerging and depicting a more complex pain representation in ALS. Pain has been detected even a couple years before the symptomatic stage of ALS, referring to primary pain associated with muscle denervation, although secondary pain due to nociceptive causes is also a part of the clinical picture. A new non-contact dying-back injury mechanism theory of ALS recently postulated that the irreversible intrafusal proprioceptive Piezo2 microinjury could be the primary damage, with underlying genetic and environmental risk factors. Moreover, this Piezo2 primary damage is also proposed to dysregulate the primary pain pathways in the spinal dorsal horn in ALS due to the lost imbalanced subthreshold Ca currents, NMDA activation and lost L-type Ca currents, leading to the lost activation of wide dynamic range neurons. Our investigation is the first to show that the likely pathogenic variants of the Ca1.3 encoding gene may play a role in ALS pathology and the associated dysregulation or loss of the pain sensation. Furthermore, our reanalysis also shows that the gene might also contribute to the dysregulated pain sensation in ALS. Finally, the absence of pathogenic variants of Piezo2 points toward the new non-contact dying-back injury mechanism theory of ALS. However, molecular and genetic investigations are needed to identify the functionally diverse features of this proposed novel critical pathway.
肌萎缩侧索硬化症（ALS）是一种致命的多系统神经退行性疾病，与运动神经元的进行性丧失相关，最终导致死亡。ALS的临床表现不仅具有异质性，而且由于疼痛类型的不同，其疼痛感觉也存在差异。ALS曾被认为是一种无痛疾病，但越来越多的研究表明，ALS中的疼痛表现更为复杂。在ALS症状出现前几年就已检测到疼痛，这与肌肉失神经支配相关的原发性疼痛有关，尽管伤害性原因导致的继发性疼痛也是临床表现的一部分。最近提出的一种新的ALS非接触性逆行性损伤机制理论认为，不可逆的肌梭内本体感受Piezo2微损伤可能是主要损伤，同时存在潜在的遗传和环境风险因素。此外，由于阈下钙电流失衡、NMDA激活丧失和L型钙电流丧失，这种Piezo2原发性损伤还被认为会导致ALS脊髓背角的原发性疼痛通路失调，进而导致广动力范围神经元的激活丧失。我们的研究首次表明，编码Ca1.3的基因的可能致病变异可能在ALS病理及相关的疼痛感觉失调或丧失中起作用。此外，我们的重新分析还表明，该基因可能也与ALS中疼痛感觉失调有关。最后，Piezo2没有致病变异这一点指向了新的ALS非接触性逆行性损伤机制理论。然而，需要进行分子和基因研究来确定这一提出的新关键通路的功能多样性特征。
