Anti-Na+/K+-ATPase immunotherapy ameliorates α-synuclein pathology through activation of Na+/K+-ATPase α1-dependent autophagy

Na+/K+-ATPase (NKA) plays important roles in maintaining cellular homeostasis. Conversely, reduced NKA activity has been reported in aging and neurodegenerative diseases. However, little is known about the function of NKA in the pathogenesis of Parkinson's disease (PD). Here, we report that reduction of NKA activity in NKA alpha 1(+/-) mice aggravates alpha-synuclein-induced pathology, including a reduction in tyrosine hydroxylase (TH) and deficits in behavioral tests for memory, learning, and motor function. To reverse this effect, we generated an NKA-stabilizing monoclonal antibody, DR5-12D, against the DR region ((897)DVEDSYGQQWTYEQR(911)) of the NKA alpha 1 subunit. We demonstrate that DR5-12D can ameliorate alpha-synuclein-induced TH loss and behavioral deficits by accelerating alpha-synuclein degradation in neurons. The underlying mechanism for the beneficial effects of DR5-12D involves activation of NKA alpha 1-dependent autophagy via increased AMPK/mTOR/ULK1 pathway signaling. Cumulatively, this work demonstrates that NKA activity is neuroprotective and that pharmacological activation of this pathway represents a new therapeutic strategy for PD.

Automated summary

Reduced NKA activity exacerbates Parkinson's disease, but the NKA-stabilizing monoclonal antibody DR5-12D can ameliorate this effect by accelerating alpha-synuclein degradation in neurons, ultimately improving tyrosine hydroxylase loss and behavioral deficits. The beneficial effects of DR5-12D involve activation of NKA alpha 1-dependent autophagy through increased AMPK/mTOR/ULK1 pathway signaling.