PERK REGULATES CALCIUM DYNAMICS IN COGNITION AND NEURODEGENERATIVE DISEASE
Open Access
- Author:
- Zhu, Siying
- Graduate Program:
- Cell and Developmental Biology
- Degree:
- Doctor of Philosophy
- Document Type:
- Dissertation
- Date of Defense:
- June 10, 2015
- Committee Members:
- Douglas Cavener, Dissertation Advisor/Co-Advisor
- Keywords:
- PERK
calcium dynamics
working memory
Alzheimer's disease - Abstract:
- PERK (EIF2AK3), an ER-resident eIF2α kinase, is well known for its role in eIF2α-dependent protein synthesis and translational control. Recent study in insulin-secreting β-cells revealed that PERK regulates Ca2+ dynamics in β-cells, which underlies glucose-stimulated insulin secretion and is protein synthesis-independent. In my thesis, motivated by PERK’s acute regulation of Ca2+ dynamics in β-cells, I explored if PERK also regulates Ca2+ dynamics in pyramidal neurons, and whether this regulation plays any physiological role in the central nervous system. I found that acute PERK inhibition by the use of a highly specific PERK inhibitor reduced Gq protein-coupled intracellular Ca2+ rise in cortical pyramidal neurons. Further experiments revealed that PERK inhibition increased IP3 receptor mediated ER Ca2+ release, but decreased receptor-operated Ca2+ entry from extracellular space. Working memory is a cognitive function that is independent of new protein synthesis, but heavily relies on Ca2+ dynamics. I identified working memory deficit in forebrain-specific Perk knockout and pharmacologically PERK-inhibited mice, suggesting that PERK’s acute regulation of Ca2+ dynamics may play a critical role in cognition. Alzheimer’s disease is an age-related neurodegenerative disease characterized by abnormal aggregation of amyloid-β peptides in the cortex and hippocampus. PERK has been speculated to regulate Alzheimer’s disease progression by its eIF2α-dependent protein synthesis and translational control. To test this hypothesis, I ablated Perk in the forebrain of an Alzheimer’s disease mouse model. I found that knocking down PERK in the forebrain alleviated the Alzheimer’s disease mice’s behavior deficits, but did not affect the amyloid-β plaque density or the expression of amyloid precursor protein and amyloid-β peptides in their forebrain. In addition, acute PERK inhibition corrected the exaggerated Gq protein-coupled Ca2+ signaling in primary neurons cultured from the Alzheimer’s disease mice model. Considering the important role of Ca2+ signaling in Alzheimer’s disease progression, it is possible that PERK regulates the disease progression by Ca2+ modulation. Taken together, in my thesis work, I discovered that PERK acutely regulates Gq protein-coupled Ca2+ dynamics in pyramidal neurons, and PERK’s modulation of Ca2+ dynamics may be directly connected to its regulation of working memory and its role in Alzheimer’s disease progression. My thesis work illustrates a novel role of PERK in the central nervous system that is eIF2α-independent, and suggests that PERK’s regulation of Ca2+ dynamics may play important physiological roles in the central nervous system.