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