Perk Genetic Variation and Function in Progressive Supranuclear Palsy

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

Error and Attack Tolerance of Layered Complex Networks

Many complex systems may be described not by one, but by a number of complex networks mapped one on the other in a multilayer structure. The interactions and dependencies between these layers cause that what is true for a distinct single layer does not necessarily reflect well the state of the entire system. In this paper we study the robustness of three real-life examples of two-layer complex systems that come from the fields of communication (the Internet), transportation (the European railway system) and biology (the human brain). In order to cover the whole range of features specific to these systems, we focus on two extreme policies of system's response to failures, no rerouting and full rerouting. Our main finding is that multilayer systems are much more vulnerable to errors and intentional attacks than they seem to be from a single layer perspective.Comment: 5 pages, 3 figure

Engrosamiento de la pared de la aorta. Utilidad de la multi imagen en el diagnóstico diferencial

A 68-year-old hypertensive female patient consulted for nonspecific chest discomfort with a normal electrocardiogram. The echocardiogram revealed aortic dilation with moderate aortic regurgitation and aortic wall thickening, without regional disorders of parietal motility. A transesophageal echocardiogram was performed, ruling out acute aortic syndrome. An angiotomography evaluation was done, suggesting an inflammatory process in the aorta and ruling out coronary involvement. For better tissue characterization of the aortic wall, gadolinium-enhanced MRI was requested, which was compatible with aortitis. The data from the clinical and laboratory history oriented the diagnosis to Giant Cell Arteritis, and treatment was started with good response.Paciente femenina de 68 años, hipertensa, consultó por molestia torácica inespecífica, con electrocardiograma normal. En el ecocardiograma se evidenció dilatación aórtica con insuficiencia aórtica moderada y engrosamiento mural aórtico, sin trastornos regionales de la motilidad. Se realizó ecocardiograma transesofágico que descartó síndrome aórtico agudo. Se continuó valoración con angiotomografía que sugirió proceso inflamatorio de la aorta y descartó compromiso coronario. Para mejor caracterización tisular de la pared aórtica se solicitó Resonancia Magnética, que resultó compatible con aortitis. Los datos de la historia clínica orientaron el diagnóstico a Arteritis de Células Gigantes, y se inició tratamiento con buena respuesta

The unfolded protein response is activated in disease-affected brain regions in progressive supranuclear palsy and Alzheimer’s disease

Abstract Background 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. Here, we evaluate UPR PERK activation in the pons, medulla, midbrain, hippocampus, frontal cortex and cerebellum in subjects with PSP, AD, and in normal controls. Results 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 haplotype associated with increased PERK activation is genetically associated with increased PSP risk. Conclusions The UPR is activated in disease affected regions in PSP and the genetic evidence shows that this activation increases risk for PSP and is not a protective response. </jats:sec