title: Early Neurodegeneration in the Brain of a Child Without Functional PKR-like Endoplasmic Reticulum Kinase.
abstract: We report the first detailed examination of the brain of a patient with Wolcott-Rallison syndrome. Wolcott-Rallison syndrome is an extremely rare clinical manifestation of a lack of protein kinase R-like endoplasmic reticulum kinase (PERK) function caused by mutations in the PERK gene EIF2AK3. Protein kinase R-like endoplasmic reticulum kinase is thought to play a significant pathogenetic role in several neurodegenerative diseases, including Alzheimer disease, other tauopathies, and Parkinson disease. The brain of a male patient aged 4 years 7 months showed pathologic and immunohistochemical evidence that the absence of PERK for several years is sufficient to induce early changes reminiscent of various neurodegenerative conditions. These include neurofibrillary tangles (as in progressive supranuclear palsy), FUS-immunopositive and p62-immunopositive neurons, and reactive glial changes. We also detected an increased amount of p62-positive puncta coimmunostaining for LC3 and ubiquitin, suggesting changes in autophagic flux. Studying a human brain with absent PERK function presents the opportunity to assess the long-term consequences of nonfunctioning of PERK in the presence of all of the compensatory mechanisms that are normally active in a living human, thereby confirming the importance of PERK for autophagy in the brain and for neurodegeneration.
authors.affiliation: From the Department of Translational Neurodegeneration, German Center for Neurodegenerative Diseases (DZNE) Munich (JB, CK, GUH); Department of Neurology, Technische Universität München (JB, CK, GUH); Department of Psychiatry and Psychotherapy (TA) and Center for Neuropathology and Prion Research (TA), Ludwig Maximilians Universität, Munich, Germany; and Department of Pathology and Neuropathology, Groupement Hospitalier Est, Bron (AV), and Division of Pediatric Endocrinology, Lyon University Pediatric Hospital, Lyon (MN), France.
authors.forename: Julius
authors.initials: J
authors.lastname: Bruch
authors.forename: Carolin
authors.initials: C
authors.lastname: Kurz
authors.forename: Alexandre
authors.initials: A
authors.lastname: Vasiljevic
authors.forename: Marc
authors.initials: M
authors.lastname: Nicolino
authors.forename: Thomas
authors.initials: T
authors.lastname: Arzberger
authors.forename: Günter U
authors.initials: GU
authors.lastname: Höglinger
mesh_terms: D001921:Brain / Q000473:pathology*; D002675:Child, Preschool; D003922:Diabetes Mellitus, Type 1 / Q000235:genetics / Q000473:pathology*; D004838:Epiphyses / Q000002:abnormalities* / Q000473:pathology; D005455:Fluorescent Antibody Technique; D006801:Humans; D007150:Immunohistochemistry; D008297:Male; D009410:Nerve Degeneration / Q000235:genetics / Q000473:pathology*; D010009:Osteochondrodysplasias / Q000235:genetics / Q000473:pathology*; D019892:eIF-2 Kinase / Q000172:deficiency*
chemical_list: C460640:EIF2AK3 protein, human; D019892:eIF-2 Kinase