Pallidal neuronal apolipoprotein E in pantothenate kinase-associated neurodegeneration recapitulates ischemic injury to the globus pallidus

Randall L. Woltjer, Lindsay C. Reese, Brian E. Richardson, Huong Tran, Sarah Green, Thao Pham, Megan Chalupsky, Isabella Gabriel, Tyler Light, Lynn Sanford, Suh Young Jeong, Jeffrey Hamada, Leila K. Schwanemann, Caleb Rogers, Allison Gregory, Penelope Hogarth, Susan J. Hayflick

Research output: Contribution to journalArticle

9 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)289-297
Number of pages9
JournalMolecular Genetics and Metabolism
Volume116
Issue number4
DOIs
StatePublished - 2015

Keywords

  • Apolipoprotein E;
  • Globus pallidus
  • Pantothenate kinase-associated neurodegeneration;

ASJC Scopus subject areas

  • Endocrinology, Diabetes and Metabolism
  • Biochemistry
  • Molecular Biology
  • Genetics
  • Endocrinology

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    Woltjer, R. L., Reese, L. C., Richardson, B. E., Tran, H., Green, S., Pham, T., Chalupsky, M., Gabriel, I., Light, T., Sanford, L., Jeong, S. Y., Hamada, J., Schwanemann, L. K., Rogers, C., Gregory, A., Hogarth, P., & Hayflick, S. J. (2015). Pallidal neuronal apolipoprotein E in pantothenate kinase-associated neurodegeneration recapitulates ischemic injury to the globus pallidus. Molecular Genetics and Metabolism, 116(4), 289-297. https://doi.org/10.1016/j.ymgme.2015.10.012