Neuroprotective Role of Akt in Hypoxia Adaptation in Andeans.

Helen Zhao,Gabriel G. Haddad,Gary Sieck,Jonathan Lin

doi:10.3389/fnins.2020.607711

Abstract

Chronic mountain sickness (CMS) is a disease that potentially threatens a large segment of high-altitude populations during extended living at altitudes above 2,500 m. Patients with CMS suffer from severe hypoxemia, excessive erythrocytosis and neurologic deficits. The cellular mechanisms underlying CMS neuropathology remain unknown. We previously showed that iPSC-derived CMS neurons have altered mitochondrial dynamics and increased susceptibility to hypoxia-induced cell death. Genome analysis from the same population identified many ER stress-related genes that play an important role in hypoxia adaptation or lack thereof. In the current study, we showed that iPSC-derived CMS neurons have increased expression of ER stress markers Grp78 and XBP1s under normoxia and hyperphosphorylation of PERK under hypoxia, alleviating ER stress does not rescue the hypoxia-induced CMS neuronal cell death. Akt is a cytosolic regulator of ER stress with PERK as a direct target of Akt. CMS neurons exhibited lack of Akt activation and lack of increased Parkin expression as compared to non-CMS neurons under hypoxia. By enhancing Akt activation and Parkin overexpression, hypoxia-induced CMS neuronal cell death was reduced. Taken together, we propose that increased Akt activation protects non-CMS from hypoxia-induced cell death. In contrast, impaired adaptive mechanisms including failure to activate Akt and increase Parkin expression render CMS neurons more susceptible to hypoxia-induced cell death.

Highlights

Chronic Mountain Sickness (CMS) is a maladaptation to hypoxia that is characterized by severe hypoxemia, excessive erythrocytosis and many neurologic manifestations, including migraine, headache, mental fatigue, confusion, and memory loss
Accumulation of unfolded protein dissociates Grp 78 from endoplasmic reticulum (ER) stress sensor proteins, which activates ER stress signaling pathways including IRE1, activating transcription factor-6 (ATF6) and PERK. Both IRE1 and PERK pathways are widely explored and play a critical role in cell death (Szegezdi et al, 2006; Iurlaro et al, 2017). We focused on these two pathways and compared the expression of XBP1s, marker of inositol-requiring protein-1 (IRE1) pathway, and pPERK/PERK, markers of protein kinase RNA (PKR)-like ER kinase (PERK) pathway, in both Chronic mountain sickness (CMS) and non-CMS groups
Enhanced Akt Activation and Parkin Overexpression Protect CMS Neurons From Hypoxia-Induced Cell Death. Since both Akt activation and Parkin overexpression are protective mechanisms, we examined whether lack of Akt activation or Parkin overexpression in CMS neurons leads to an increased susceptibility to hypoxia injury and cell death, we treated CMS neurons with (1) Akt agonist and (2) an overexpression of Parkin with hypoxia for 48 h

Summary

Introduction

Chronic Mountain Sickness (CMS) is a maladaptation to hypoxia that is characterized by severe hypoxemia, excessive erythrocytosis and many neurologic manifestations, including migraine, headache, mental fatigue, confusion, and memory loss. Since hypoxia is a common feature of many diseases at sea level including cardiovascular diseases, neurodegenerative diseases, stroke, diabetes and cancer, we believe that investigating the underlying mechanisms of hypoxia maladaptation or adaptation in CMS and non-CMS subjects may lead us to a better understanding of many hypoxia-related diseases as well. Role of Akt in Hypoxia Adaptation in humans remains largely unexplored at cellular and molecular levels. By using CMS disease-specific iPSC-derived neurons, we have previously reported mitochondrial dysfunction in CMS neurons under normoxia and an increased vulnerability to hypoxia-induced cell death after 48 h (Zhao et al, 2018). We are interested in investigating the underlying mechanisms that contribute to hypoxia-induced cell death in CMS neurons

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