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bioRxiv · 10.64898/2026.03.09.709927

Neuronal overexpression of mouse potassium channel subunit Kcnn1 in A53T α-synuclein mice more than doubles median survival time, associated with suppression of phospho-S129 α-synuclein formation

Nagy, M.·Fenton, W. A.·Horwich, A. L.
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Abstract

Synucleinopathies, including idiopathic Parkinsons Disease, are driven by misfolding and aggregation of the 140 residue -synuclein protein that plays a role in presynaptic vesicle regulation. We describe effects of a modifier, neuronal overexpression of the mouse calcium-activated potassium channel subunit Kcnn1, on a mouse model in which transgenic Thy1.2-driven A53T -synuclein directs fully penetrant lethal motor disease. Kcnn1 overexpression increased median survival of these mice from 8.5 months to 18 months, associated with an altered clinical presentation from a rapidly progressive dystonic-like behavior of the limbs to a later-onset (12-16 mo) and slowly progressive lower limb clasping when lifted by the tail. At the tissue level, accretion of disease-associated phospho-serine 129 -synuclein was prevented by overexpression of Thy1.2-driven Kcnn1, which was observed in many brain regions, including the ones where phospho-serine 129 -synuclein was copiously accreted in A53T mice at endstage. The action of blocking production of phospho-serine 129 -synuclein was also observed in adult presymptomatic A53T mice injected with an AAV9 scCMV-Kcnn1 virus into the right superior colliculus. At endstage [~]2 months later, the right superior colliculus exhibited overexpression of Kcnn1 and showed essentially no phospho-serine 129 -synuclein, whereas the uninjected left superior colliculus exhibited copious phospho-serine 129 -synuclein. The neuroprotective action of Kcnn1 overexpression remains to be fully resolved, but the channel protein subunit, targeted to the ER membrane, has been shown to induce an ER stress response. This response, which may activate autophagy, along with potential channel formation, may diminish the rate of formation or lifetime of neurotoxic forms of A53T -synuclein.

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Nagy, M., Fenton, W. A., Horwich, A. L.. 2026-03-11. Neuronal overexpression of mouse potassium channel subunit Kcnn1 in A53T α-synuclein mice more than doubles median survival time, associated with suppression of phospho-S129 α-synuclein formation. https://doi.org/10.64898/2026.03.09.709927

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