title: Pallidal neuronal apolipoprotein E in pantothenate kinase-associated neurodegeneration recapitulates ischemic injury to the globus pallidus.
abstract: Pantothenate kinase-associated neurodegeneration (PKAN) is a progressive movement disorder that is due to mutations in PANK2. Pathologically, it is a member of a class of diseases known as neurodegeneration with brain iron accumulation (NBIA) and features increased tissue iron and ubiquitinated proteinaceous aggregates in the globus pallidus. We have previously determined that these aggregates represent condensed residue derived from degenerated pallidal neurons. However, the protein content, other than ubiquitin, of these aggregates remains unknown. In the present study, we performed biochemical and immunohistochemical studies to characterize these aggregates and found them to be enriched in apolipoprotein E that is poorly soluble in detergent solutions. However, we did not determine a significant association between APOE genotype and the clinical phenotype of disease in our database of 81 cases. Rather, we frequently identified similar ubiquitin- and apolipoprotein E-enriched lesions in these neurons in non-PKAN patients in the penumbrae of remote infarcts that involve the globus pallidus, and occasionally in other brain sites that contain large γ-aminobutyric acid (GABA)ergic neurons. Our findings, taken together, suggest that tissue or cellular hypoxic/ischemic injury within the globus pallidus may underlie the pathogenesis of PKAN.
authors.affiliation: Department of Pathology, Oregon Health & Science University, Portland, OR 97239, United States. Electronic address: woltjerr@ohsu.edu.
authors.forename: Randall L
authors.initials: RL
authors.lastname: Woltjer
authors.affiliation: Department of Pathology, Oregon Health & Science University, Portland, OR 97239, United States.
authors.forename: Lindsay C
authors.initials: LC
authors.lastname: Reese
authors.affiliation: Department of Molecular and Medical Genetics, Oregon Health & Science University, Portland, OR 97239, United States.
authors.forename: Brian E
authors.initials: BE
authors.lastname: Richardson
authors.affiliation: Department of Pathology, Oregon Health & Science University, Portland, OR 97239, United States.
authors.forename: Huong
authors.initials: H
authors.lastname: Tran
authors.affiliation: Department of Pathology, Oregon Health & Science University, Portland, OR 97239, United States.
authors.forename: Sarah
authors.initials: S
authors.lastname: Green
authors.affiliation: Department of Pathology, Oregon Health & Science University, Portland, OR 97239, United States.
authors.forename: Thao
authors.initials: T
authors.lastname: Pham
authors.affiliation: Department of Pathology, Oregon Health & Science University, Portland, OR 97239, United States.
authors.forename: Megan
authors.initials: M
authors.lastname: Chalupsky
authors.affiliation: Department of Pathology, Oregon Health & Science University, Portland, OR 97239, United States.
authors.forename: Isabella
authors.initials: I
authors.lastname: Gabriel
authors.affiliation: Department of Pathology, Oregon Health & Science University, Portland, OR 97239, United States.
authors.forename: Tyler
authors.initials: T
authors.lastname: Light
authors.affiliation: Department of Molecular and Medical Genetics, Oregon Health & Science University, Portland, OR 97239, United States.
authors.forename: Lynn
authors.initials: L
authors.lastname: Sanford
authors.affiliation: Department of Molecular and Medical Genetics, Oregon Health & Science University, Portland, OR 97239, United States.
authors.forename: Suh Young
authors.initials: SY
authors.lastname: Jeong
authors.affiliation: Department of Molecular and Medical Genetics, Oregon Health & Science University, Portland, OR 97239, United States.
authors.forename: Jeffrey
authors.initials: J
authors.lastname: Hamada
authors.affiliation: Department of Molecular and Medical Genetics, Oregon Health & Science University, Portland, OR 97239, United States.
authors.forename: Leila K
authors.initials: LK
authors.lastname: Schwanemann
authors.affiliation: Department of Molecular and Medical Genetics, Oregon Health & Science University, Portland, OR 97239, United States.
authors.forename: Caleb
authors.initials: C
authors.lastname: Rogers
authors.affiliation: Department of Molecular and Medical Genetics, Oregon Health & Science University, Portland, OR 97239, United States.
authors.forename: Allison
authors.initials: A
authors.lastname: Gregory
authors.affiliation: Department of Molecular and Medical Genetics, Oregon Health & Science University, Portland, OR 97239, United States.
authors.forename: Penelope
authors.initials: P
authors.lastname: Hogarth
authors.affiliation: Department of Molecular and Medical Genetics, Oregon Health & Science University, Portland, OR 97239, United States.
authors.forename: Susan J
authors.initials: SJ
authors.lastname: Hayflick
mesh_terms: D001057:Apolipoproteins E / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D002545:Brain Ischemia / Q000150:complications / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D016022:Case-Control Studies; D002648:Child; D005260:Female; D059330:GABAergic Neurons / Q000737:chemistry* / Q000378:metabolism / Q000473:pathology; D015870:Gene Expression; D005917:Globus Pallidus / Q000378:metabolism / Q000473:pathology; D006801:Humans; D008297:Male; D008875:Middle Aged; D009154:Mutation; D006211:Pantothenate Kinase-Associated Neurodegeneration / Q000150:complications / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D017853:Phosphotransferases (Alcohol Group Acceptor) / Q000172:deficiency / Q000235:genetics*; D066263:Protein Aggregation, Pathological / Q000150:complications / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D025801:Ubiquitin / Q000737:chemistry / Q000235:genetics / Q000378:metabolism
chemical_list: D001057:Apolipoproteins E; D025801:Ubiquitin; D017853:Phosphotransferases (Alcohol Group Acceptor); C023088:pantothenate kinase
keywords: Apolipoprotein E;; Globus pallidus; Pantothenate kinase-associated neurodegeneration;