Kynurenine Pathway Dysregulation—Watch out for Acquired Piezo2 Channelopathy

The current opinion paper puts forward how acquired Piezo2 channelopathy may explain the onset of kynurenine pathway dysregulation, a common underlying pathophysiology of neurodegenerative diseases. Accordingly, acquired Piezo2 channelopathy-induced proton affinity switch or proton reversal and resultant oxidative phosphorylation impairment may not allow proton abstraction from heme proteins, like indoleamine 2,3-dioxygenase and TRP 2,3-dioxygenase, leading to tryptophan accumulation and dysregulated kynurenine pathway. The consequential tryptophan accumulation may not only reduce cell membrane stress tolerance, increases cholesterol precipitation and decreases phosphatidylinositol 4,5-bisphosphate, but might even impair the underappreciated intrinsic disorder function of Piezo2 chronically.