Acquired Piezo2 Channelopathy is the Gateway to Condensopathies of Stress Granules, Like in Amyotrophic Lateral

Recent amyotrophic lateral sclerosis (ALS) related paper raised the possibility of a common underlying mechanism that impairs membrane organelle function, like the one leading to the toxicity of C9orf72-derived arginine-rich dipeptide repeats in the affected cells. The current opinion piece proposes that the principally affected cells are glutamatergic fibers on which cell-autonomous neuron-specific processes may prevail leading to neurodegeneration, as an ALS-based genome-like association study revealed it. Moreover, these glutamatergic fibers are suggested to be Type Ia proprioceptive neurons in the case of ALS and the gateway to pathophysiology is proposed to be the irreversible Piezo2 channelopathy of these terminals. These Piezo2-containing glutamatergic fibers in a given compartment, like the Type Ia proprioceptive one in the muscle spindle, may regulate neighboring Piezo1-containing cells through Piezo2-Piezo1 crosstalk, not only functionally, but metabolically as well. Finally, the underlying gateway to pathophysiology, leading to acquired Piezo2 channolapthy is suggested to be a proton affinity switch or proton reversal on Piezo2, as the current paper proposes that this proton reversal impairs membrane organelle function downstream. Similar pathogenic derailment of liquid-liquid phase separation with possible underlying linked mechanism could be experienced in several diseases, like cancer, inflammation, virus infection and neurodegeneration, collectively coined as “condensopathies”. Accordingly, the current author proposes that acquired chronic or irreversible Piezo2channelopathy-induced proton reversal of glutamatergic somatosensory terminals may constitute the common underlying initiating switch mechanism, leading to the pathogenic derailment of liquid-liquid phase separation of condesopathies, like is proposed in ALS.