Recent Advances in the Study of Na+/K+-ATPase in Neurodegenerative Diseases

Abstract

Na⁺/K⁺-ATPase (NKA), a large transmembrane protein, is expressed in the plasma membrane of most eukaryotic cells. It maintains resting membrane potential, cell volume and secondary transcellular transport of other ions and neurotransmitters. NKA consumes about half of the ATP molecules in the brain, which makes NKA highly sensitive to energy deficiency. Neurodegenerative diseases (NDDs) are a group of diseases characterized by chronic, progressive and irreversible neuronal loss in specific brain areas. The pathogenesis of NDDs is sophisticated, involving protein misfolding and aggregation, mitochondrial dysfunction and oxidative stress. The protective effect of NKA against NDDs has been emerging gradually in the past few decades. Hence, understanding the role of NKA in NDDs is critical for elucidating the underlying pathophysiology of NDDs and identifying new therapeutic targets. The present review focuses on the recent progress involving different aspects of NKA in cellular homeostasis to present in-depth understanding of this unique protein. Moreover, the essential roles of NKA in NDDs are discussed to provide a platform and bright future for the improvement of clinical research in NDDs.

Keywords: Na+/K+-ATPase; mitochondrial dysfunction; neurodegenerative diseases; oxidative stress; protein–protein interaction.

Figure 1

Schematic illustration of NKA structure. NKA contains the α, β and γ subunits. The extracellular region⁸⁹⁷ DVEDSYGQQWTYEQR⁹¹¹ (DR region) of the α subunit is associated with the β subunit. The hexagons (yellow and red) depicted above are two binding sites for α-synuclein fibrils and spherical amyloid β (Aβ) oligomers that are close to the DR region [25,26].

Figure 2

Schematic illustration showing how ASPD secretion from the excitatory neurons induces neuronal loss and vascular pathologies. In response to central nervous system (CNS) damage, astrocytic NKAα2 level was upregulated and contributed to astrogliosis [59]. The activated astrocytes then secreted more proinflammatory protein lipocalin-2 (Lcn-2) to neurons, causing neurons to uptake more extracellular tau and resulting in the formation of the neurofibrillary tangles [59].

Figure 3

Interactions between α-syn and NKA α subunit in the extracellular and intracellular segments. Left panel: α-syn bound to the neuronal membrane and formed a complex with NKAα3. This complex impaired NKAα3 activity and increased glutamate-induced Ca²⁺ influx to induce neuronal loss. Right panel: Intracellular part of NKAα1 formed a complex with α-syn/AMPKα to translocate AMPKα to the plasma membrane. DR5-12D prevented the formation of this complex and alleviated the symptoms of PD.