Parkinson’s Disease Onset in Light of Acquired Irreversible Piezo2 Channelopathy
Parkinson’s Disease Onset in Light of Acquired Irreversible Piezo2 Channelopathy
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Original abstract
Neurodegenerative diseases posit a global challenge due to their aging-dependent increasing incidence around the world. The three most prevalent one, namely Alzheimer’s disease, Parkinson’s disease and amyotrophic lateral sclerosis are multisystem, progressive and degenerative diseases with underlying environmental and genetic risk factors. Not a single common initiating cause had been attributed to these neurodegenerative diseases due to their multifactorial disease background. Acquired irreversible Piezo2 channelopathy was first proposed as such a primary microdamage in the case of ALS in 2022, and later in the case of Alzheimer’s disease. Even though it has been suggested in 2025 that the impairment of the ultrafast ultradian cerebellar-hippocampal axis may initiate Parkinson’s disease due to acquired irreversible Piezo2 channelopathy, but detailed mechanistic introduction has been at need. Therefore, the current manuscript meant to introduce how the Piezo2-containing cerebellar Purkinje cells and deep cerebellar nuclei, more specifically dentate nuclei, principally fine-modulates the dopamine release of the neurons of substantia nigra pars compacta, initiates an ultrafast intermittent control strategy of postural control, and initiates beta and cerebellar theta synchronization. Consequently, the acquired irreversible Piezo2 channelopathy of the cells of deep cerebellar nuclei may initiate Parkinson’s disease onset by terminally impairing the fine-regulation of dopamine release, the intermittent cerebellar control strategy, the ultrafast ultradian cerebellar-hippocampal axis in association with energy generation switch from OXPHOS during acute stress responses.