Secretariat, Alumni Association, IDAC
Date Thursday, 4 July 2019, 17:30 to 18:30
Room Seminar Room, Center for Smart Aging Research 2F, IDAC
Title Na+, K+-ATPase α3 is a NEW death target of Alzheimer amyloid-β assembly.
Speaker Hoshi Minako
Affiliation Professor, Department of Brain and Neurodegenerative Disease Research,
Institute of Biomedical Research and Innovation Foundation for Biomedical Research and Innovation at Kobe
Organizer Yasuyuki Taki
Co-Deputy Director, Smart-Aging Research Center, Tohoku University Professor, Department of Nuclear Medicine and Radiology, Institute of Development, Aging and Cancer, Tohoku University, ext 8582
Abstract Alzheimer’s disease (AD) impairs cognitive function, initially by affecting neuronal synaptic connections and eventually by degeneration of neurons themselves. This brain damage is thought to be caused by a small protein, the amyloid b-protein (Ab), which becomes neurotoxic by forming varieties of assemblies, collectively referred to “Ab oligomers.” Our laboratory has long been focusing on understanding mechanisms of neurodegeneration in AD and has identified Ab oligomer from AD patient brains, termed amylospheroids (ASPD), as responsible for neurodegeneration (Hoshi et al. PNAS2003, Noguchi et al. JBC2009). Then, we discovered that the neuron-specific a3 subunit of the Na+, K+-ATPase pump (NAKa3), the catalytic subunit that is essential for neuronal excitability, is a toxic target for ASPD (Ohnishi et al. PNAS2015). This is a new system that involves pre-synaptic calcium hyperactivation, which is triggered by impairing NAKa3-derived NAK pump activity, leading to neurodegeneration (Figure 1). Before this finding, NAKa3 had long been considered to be too essential to be the cause of neurodegenerative disease. However, following our finding, the impairment of NAKa3 owing to the binding with misfolded protein assemblies were reported in Parkinson’s disease (Shrivastava et al. EMBO J 34, 2408-2423, 2015) and ALS (Ruegsegger et al. Act Neuropathlogy 131, 427-451, 2016). This suggested that the NAKa3 impairment might be a general pathway leading to neurodegenerative diseases. We also discovered that ASPD-binding tetrapeptides blocked the ASPD:NAKa3 interaction and protected mature neurons from ASPD neurotoxicity. Surprisingly, ASPD and a-synuclein share the essential binding region in the fourth extracellular loop of NAKa3. I thus have suggested that a new AD treatment strategy might be based on blocking aberrant ASPD-NAKa3 interaction by masking the ASPD surface with specific peptidomimetics, as shown in figure 2. Recently, we started a collaboration with Dr Chikashi Toyoshima from University of Tokyo who determined the crystal structures of Ca-ATPase and NAKa1. Because ASPD binds the region essential for the rocking motion of the NAKa3 pump, it is reasonable that ASPD binding impairs NAKa3 function. At the seminar, I would be happy to discuss about what we shall do as a next to uncover distribution and function of NAKa3 in health and disease.