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

Mol Genet Metab. 2015 Dec;116(4):289-97. doi: 10.1016/j.ymgme.2015.10.012. Epub 2015 Oct 31.


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.

Keywords: Apolipoprotein E;; Globus pallidus; Pantothenate kinase-associated neurodegeneration;.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Apolipoproteins E / chemistry*
  • Apolipoproteins E / genetics
  • Apolipoproteins E / metabolism
  • Brain Ischemia / complications
  • Brain Ischemia / genetics*
  • Brain Ischemia / metabolism
  • Brain Ischemia / pathology
  • Case-Control Studies
  • Child
  • Female
  • GABAergic Neurons / chemistry*
  • GABAergic Neurons / metabolism
  • GABAergic Neurons / pathology
  • Gene Expression
  • Globus Pallidus / metabolism
  • Globus Pallidus / pathology
  • Humans
  • Male
  • Middle Aged
  • Mutation
  • Pantothenate Kinase-Associated Neurodegeneration / complications
  • Pantothenate Kinase-Associated Neurodegeneration / genetics*
  • Pantothenate Kinase-Associated Neurodegeneration / metabolism
  • Pantothenate Kinase-Associated Neurodegeneration / pathology
  • Phosphotransferases (Alcohol Group Acceptor) / deficiency
  • Phosphotransferases (Alcohol Group Acceptor) / genetics*
  • Protein Aggregation, Pathological / complications
  • Protein Aggregation, Pathological / genetics*
  • Protein Aggregation, Pathological / metabolism
  • Protein Aggregation, Pathological / pathology
  • Ubiquitin / chemistry
  • Ubiquitin / genetics
  • Ubiquitin / metabolism


  • Apolipoproteins E
  • Ubiquitin
  • Phosphotransferases (Alcohol Group Acceptor)
  • pantothenate kinase