Progressive supranuclear palsy (PSP) is a neurodegenerative disorder pathologically characterized by intracellular tangles of hyperphosphorylated tau protein distributed throughout the neocortex, basal ganglia, and brainstem. A genome-wide association study identified EIF2AK3 as a risk factor for PSP. EIF2AK3 encodes PERK, part of the endoplasmic reticulum’s (ER) unfolded protein response (UPR). PERK is an ER membrane protein that senses unfolded protein accumulation within the ER lumen. Recently, several groups noted UPR activation in Alzheimer’s disease (AD), Parkinson’s disease (PD), amyotrophic lateral sclerosis, multiple system atrophy, and in the hippocampus and substantia nigra of PSP subjects. In Chapter 2, we evaluate PERK activation in the pons, medulla, midbrain, hippocampus, frontal cortex and cerebellum in subjects with PSP, AD, and in normal controls. We found UPR activation primarily in disease-affected brain regions in both disorders. In PSP, the UPR was primarily activated in the pons and medulla and to a much lesser extent in the hippocampus. In AD, the UPR was extensively activated in the hippocampus. We also observed UPR activation in the hippocampus of some elderly normal controls, severity of which positively correlated with both age and tau pathology but not with Aβ plaque burden. Finally, we evaluated EIF2AK3 coding variants that influence PERK activation. We show that a PERK haplotype that demonstrates increased eIF2α kinase activity is genetically associated with increased PSP risk. The UPR is activated in disease affected regions in PSP and the genetic and biological evidence shows that this activation increases risk for PSP and is not a protective response. There are two common protein coding variants of PERK, HapA and HapB, which differ by three amino acids. Recent work indicates HapB PERK has more kinase activity in response to thapsigargin treatment than does HapA in human β-lymphocytes. The goal of the work detailed in Chapter 3 was to: 1) replicate and expand upon previous findings in β-lymphocytes and 2) determine which of the three amino acid coding changes is responsible for the difference in PERK activity between HapA and HapB. This work confirms that β-lymphocytes expressing HapB PERK show more eIF2α phosphorylation than those expressing HapA. Paradoxically, HapB PERK cells also show less phosphorylated PERK. These findings were echoed in mouse embryonic fibroblasts expressing PERK variant constructs. Further work exploring the functional differences between PERK variants is warranted. Chapter 4 discusses the implications of the work detailed in Chapters 2 and 3 and suggests future directions for this work, including examination of post-translational modifications of PERK and exploration of how PERK variants function in cell culture models of tauopathy.