Likely Pathogenic Variants of Cav1.3 and Nav1.1 Encoding Genes in Amyotrophic Lateral Sclerosis Could Elucidate the Dysregulated Pain Pathways

Abstract

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 Ca2+ currents, NMDA activation and lost L-type Ca2+ 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 Cav1.3 encoding CACNA1D 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 SCN1A 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.

Progressive Irreversible Proprioceptive Piezo2 Channelopathy-Induced Lost Forced Peripheral Oscillatory Synchronization to the Hippocampal Oscillator May Explain the Onset of Amyotrophic Lateral Sclerosis Pathomechanism

“…Interestingly, syndecan-3 is implicated in the pathology of Alzheimer’s disease [ 25 ], but no relationship to ALS has been reported yet. It is important to remark that the reanalysis of the potential pathogenic gene variants from a previous ALS study confirmed the absence of pathogenic variants of Piezo2 and Piezo1 [ 15 ]. This exclusion substantiated the idea that the suggested irreversible Piezo2 channelopathy is acquired and not inherited, as was theorized in the non-contact dying-back injury mechanism theory for ALS [ 15 ].…”

“…It is important to remark that the reanalysis of the potential pathogenic gene variants from a previous ALS study confirmed the absence of pathogenic variants of Piezo2 and Piezo1 [ 15 ]. This exclusion substantiated the idea that the suggested irreversible Piezo2 channelopathy is acquired and not inherited, as was theorized in the non-contact dying-back injury mechanism theory for ALS [ 15 ]. Nevertheless, the current opinion piece theorizes that shedding or charge altering variants of the syndecan-3-encoding SDC3 gene may contribute to how the acquired irreversible Piezo2 channelopathy could evolve during the aging process, leading to the progressively lost remodeling and regeneration of the affected muscles in ALS.…”

Recent research advances in pain mechanisms in McCune–Albright syndrome thinking about the pain mechanism of FD/MAS

“…Additional studies have suggested that Piezo2 plays a role in synchronizing supraspinal neural networks [ 11 ], and the loss of excitatory function of Piezo2 may theoretically lead to impaired spinal synchrony and loss of spinal function in the central pattern generator (CPG). Pathogenic variants of Cav1.3, which encode the CACNA1D gene, may play a role in the pain mechanisms of FD/MAS and have a specific relationship with dysregulation of pain pathways in the dorsal horn of the spinal cord [ 12 ].…”

“…It plays a key role in FD/MAS pain mechanisms 2021 Hendrickx G et al [ 6 ] Mouse animal experiments Evidence that Runx2② is expressed not only in osteoblast progenitor cells but also in hypertrophic prechondrocytes suggests that Piezo1 plays a role in chondrocytes to ensure bone trabecule formation Regulates osteogenesis and cartilage degradation in the joint and promotes the process of bone remodeling 2023 Perin et al [ 13 ] Overview Triggers osteoblast differentiation and hinders lipogenic cell differentiation This mechanism affects bone remodeling. It may play a key role in FD/MAS pain mechanisms 2023 Sonkodi et al [ 9 ] Mouse animal experiments Piezo2 is essential for shifting pain and touch sensations, as well as proprioception, in the nervous system Irreversible microdamage of Piezo2 ion channels may be a major cause of MAS pain 2023 Nagy et al [ 11 ] Genome Analysis The absence of pathogenic variants of Piezo2 indicates a new theory of noncontact damage mechanisms Variants in Cav1.3 encoding the CACNA1D gene (iii) may be responsible for MAS bone pain ① YAP-dependent expression: Yes-associated protein (YAP for short), which preferentially uses fatty acid oxidation for energy supply; ② Runt-related transcription Factor 2: Runx2 plays an important role in the regulation of skeletal-related genes, which regulate the process of bone resorption, bone formation, and bone reconstruction ( in addition to regulating osteoblasts, chondrocytes, osteoclasts, and other bone cells); ③ CACNA1D is a voltage-gated calcium channel …”

LF Power of HRV Could Be the Piezo2 Activity Level in Baroreceptors with Some Piezo1 Residual Activity Contribution

“…Furthermore, this accelerated lethality in ALS is associated with terminal circulatory and respiratory collapse and might not be due only to muscular insufficiency. Indeed, the aforementioned proposed involvement of Cav1.3 channels in the absence of activated Piezo2 comes from a different pathway according to a recent theory based on reanalysis of an ALS genetic database [ 55 , 57 ].…”