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

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

Science advances (2021-02-12)
Lei Cao, Siping Xiong, Zhiyuan Wu, Lei Ding, Yebo Zhou, Haijian Sun, Mengyuan Zhu, Wei Thye Lee, Xiaowei Nie, Jin-Song Bian
ABSTRACT

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 NKAα1+/- mice aggravates α-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 (897DVEDSYGQQWTYEQR911) of the NKAα1 subunit. We demonstrate that DR5-12D can ameliorate α-synuclein-induced TH loss and behavioral deficits by accelerating α-synuclein degradation in neurons. The underlying mechanism for the beneficial effects of DR5-12D involves activation of NKAα1-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.

MATERIALS
Product Number
Brand
Product Description

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Freund′s Adjuvant, Complete, cell suspension
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Freund′s Adjuvant, Incomplete, liquid
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Ouabain octahydrate, ≥95% (HPLC), powder
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Pristane, synthetic, ≥98% (GC)
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Phosphate Colorimetric Kit, sufficient for 500 colorimetric tests
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Atto 488 Protein Labeling Kit