TY - JOUR
T1 - Pallidal neuronal apolipoprotein E in pantothenate kinase-associated neurodegeneration recapitulates ischemic injury to the globus pallidus
AU - Woltjer, Randall L.
AU - Reese, Lindsay C.
AU - Richardson, Brian E.
AU - Tran, Huong
AU - Green, Sarah
AU - Pham, Thao
AU - Chalupsky, Megan
AU - Gabriel, Isabella
AU - Light, Tyler
AU - Sanford, Lynn
AU - Jeong, Suh Young
AU - Hamada, Jeffrey
AU - Schwanemann, Leila K.
AU - Rogers, Caleb
AU - Gregory, Allison
AU - Hogarth, Penelope
AU - Hayflick, Susan J.
N1 - Publisher Copyright:
© 2015 Elsevier Inc. All rights reserved.
PY - 2015
Y1 - 2015
N2 - 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.
AB - 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.
KW - Apolipoprotein E;
KW - Globus pallidus
KW - Pantothenate kinase-associated neurodegeneration;
UR - http://www.scopus.com/inward/record.url?scp=84961602261&partnerID=8YFLogxK
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U2 - 10.1016/j.ymgme.2015.10.012
DO - 10.1016/j.ymgme.2015.10.012
M3 - Article
C2 - 26547561
AN - SCOPUS:84961602261
SN - 1096-7192
VL - 116
SP - 289
EP - 297
JO - Molecular Genetics and Metabolism
JF - Molecular Genetics and Metabolism
IS - 4
ER -