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

Abstract

Amyotrophic lateral sclerosis (ALS) is a mysterious lethal multisystem neurodegenerative disease that gradually leads to the progressive loss of motor neurons. A recent non-contact dying-back injury mechanism theory for ALS proposed that the primary damage is an acquired irreversible intrafusal proprioceptive terminal Piezo2 channelopathy with underlying genetic and environmental risk factors. Underpinning this is the theory that excessively prolonged proprioceptive mechanotransduction under allostasis may induce dysfunctionality in mitochondria, leading to Piezo2 channelopathy. This microinjury is suggested to provide one gateway from physiology to pathophysiology. The chronic, but not irreversible, form of this Piezo2 channelopathy is implicated in many diseases with unknown etiology. Dry eye disease is one of them where replenishing synthetic proteoglycans promote nerve regeneration. Syndecans, especially syndecan-3, are proposed as the first critical link in this hierarchical ordered depletory pathomechanism as proton-collecting/distributing antennas; hence, they may play a role in ALS pathomechanism onset. Even more importantly, the shedding or charge-altering variants of Syndecan-3 may contribute to the Piezo2 channelopathy-induced disruption of the Piezo2-initiated proton-based ultrafast long-range signaling through VGLUT1 and VGLUT2. Thus, these alterations may not only cause disruption to ultrafast signaling to the hippocampus in conscious proprioception, but could disrupt the ultrafast proprioceptive signaling feedback to the motoneurons. Correspondingly, an inert Piezo2-initiated proton-based ultrafast signaled proprioceptive skeletal system is coming to light that is suggested to be progressively lost in ALS. In addition, the lost functional link of the MyoD family of inhibitor proteins, as auxiliary subunits of Piezo2, may not only contribute to the theorized acquired Piezo2 channelopathy, but may explain how these microinjured ion channels evolve to be principal transcription activators.

Commentary: Effects of combined treatment with transcranial and peripheral electromagnetic stimulation on performance and pain recovery from delayed onset muscle soreness induced by eccentric exercise in young athletes. A randomized clinical trial

“…This theory is analogous to the earlier coupled oscillator model that suggested the entrainment of the imposed forcing intrafusal Type Ia afferent peripheral oscillator to the oscillator(s) of the central nervous system (CNS) (Cathers et al, 2006). Hence, as a result of the primary damage of DOMS, not only VGLUT1 may disconnect transiently on motoneurons, as was suggested by Sonkodi et al (2022), but also VGLUT2 disconnection could be another consequence in the CNS, leading to impaired proprioception (Sonkodi, 2023a;Sonkodi, 2024). Highly indicative of this VGLUT1/ 2 disconnection theory is the finding that motor output is misjudged and disturbed when the "exercised arm acted as its own reference" after eccentric and isometric exercise (Philippou et al, 2010).…”

“…The aforementioned simultaneous transient central synaptic disconnection of proprioceptors from motoneurons through the loss of VGLUT1/Ia synapses and VGLUT2 disconnection in the CNS due to the DOMS effect (Sonkodi, 2023a;Sonkodi, 2024) could be the missing link why only the combined TES and PES treatment is effective. Accordingly, the electromagnetic stimulation may compensate for the lost essential proton-signaled proprioceptive feedback loops on upper and lower motoneurons but only if the stimulation is conveyed on both motoneuron territories.…”

“…Frontiers in Physiology frontiersin.org 02 Sonkodi 10.3389/fphys.2024.1380261 In support of the aforementioned essentiality, the irreversibly and progressively lost function of Piezo2 in proprioceptive terminals is suggested to be one critical underlying process in the amyotrophic lateral sclerosis (ALS) pathomechanism (Sonkodi, 2021;Sonkodi and Hortobagyi, 2022;Sonkodi, 2023b;Sonkodi, 2024). Moreover, animal studies also show that Piezo2-knockout mice do not survive after delivery; hence, the homeostatic gatekeeper function of Piezo2 on somatosensory neurons is essential in order to protect the CNS (Ranade et al, 2014;Volkers et al, 2015).…”

“…An even more recent novel theory postulates that proprioceptive terminal Piezo2-initiated proton-based frequency coupling through VGLUT2 may provide a long suspected ultrafast long-range signaling for the synchronization of the low-frequency glutamatergic cell surface membrane oscillations in order to provide proprioceptive input to hippocampal theta rhythm encoding (Sonkodi, 2023a;2024). This theory is analogous to the earlier coupled oscillator model that suggested the entrainment of the imposed forcing intrafusal Type Ia afferent peripheral oscillator to the oscillator(s) of the central nervous system (CNS) (Cathers et al, 2006).…”

“…It should be noted that ASIC2 ion channels are also present on proprioceptive Type Ia terminals (Simon et al, 2010), and most likely, they provide the proton-based signaling pathway between Piezo2 and VGLUT (Sonkodi, 2024). However, the low-frequency Schottky barrier semiconductor diode feature of Piezo2 may be the one providing the control of fine movements (Sonkodi, 2023a;Sonkodi, 2024) in addition to proprioceptive signal generation, but an intimate co-functioning of Piezo2 and ASIC2 is suspected in this process (Bornstein et al, 2023;Sonkodi, 2024). Not surprisingly, lost ASIC2 function alters muscle spindle-derived stretch responses and motor coordination (Bornstein et al, 2023).…”