Neuronal overexpression of Kcnn1 in A53T α-synuclein mice suppresses phospho-serine 129 α-synuclein formation and doubles survival time

Abstract

Significance Parkinson’s Disease and several other neurodegenerative diseases are driven by misfolding and aggregation of the neuronal protein α-synuclein. We studied a transgenic mouse model expressing the Parkinson’s-associated A53T mutant human α-synuclein, that succumbs with dystonic limbs at ~8 mo, with presence of disease-associated phospho-serine 129 α-synuclein in a variety of brain regions and in the spinal cord. We identified a modifier of this clinicopathology, the neuronal overexpression of Kcnn1, a potassium channel subunit. The modified mice survived to ~18 mo, exhibited a different clinical behavior—mild lower limb clasping—and did not form any significant level of the phosphorylated α-synuclein. Overexpression of Kcnn1 thus appears to be neuroprotective. Its action may have therapeutic implications.