title: Cerebellar expression of copper chaperone for superoxide, cytosolic cu/zn-superoxide dismutase, 4-hydroxy-2-nonenal, acrolein and heat shock protein 32 in patients with menkes kinky hair disease: immunohistochemical study.
abstract: BACKGROUND
  To clarify the pathogenesis of cerebellar Purkinje cell death in patients with Menkes kinky hair disease (MD), a disorder of copper absorption, we investigated the morphological and functional abnormalities of residual Purkinje cells in MD patients and the mechanism of cell death.
  
  
  METHODS
  Seven MD patients and 39 neurologically normal autopsy cases were studied. We performed histopathological and quantitative analyses of the Purkinje cells. In addition, we used immunohistochemistry to detect copper-dependent enzymes [cytosolic Cu/Zn-superoxide dismutase (SOD1) and copper chaperone for superoxide dismutase (CCS)], oxidative stress markers [4-hydroxy-2-nonenal (HNE) and acrolein] and heat shock protein 32 (hsp 32).
  
  
  RESULTS
  The surviving MD Purkinje cells showed abnormal development, such as somatic sprouts and heterotopic location. Due to maldevelopment and degeneration, dendrites showed the cactus and weeping willow patterns. Axonal degeneration led to the formation of torpedoes. Quantitative analysis revealed loss of approximately 50% of the Purkinje cells in MD patients. Almost all of the normal Purkinje cells were positive for immunostaining by anti-CCS and anti-SOD1 antibodies, with staining of the cell bodies, dendrites and axons. Normal Purkinje cells were not stained by antibodies for HNE, acrolein or hsp 32. In MD patients, the majority of Purkinje cells were positive for CCS, but the positive rate for SOD1 was only about 23%. Approximately 56%, 42% and 40% of the Purkinje cells of MD patients were positive for HNE, acrolein and hsp 32, respectively.
  
  
  CONCLUSIONS
  In MD patients, about 50% of the Purkinje cells have been lost due to maldevelopment and degeneration. In the residual Purkinje cells, CCS expression seems to be nearly normal as a protective response to decreased SOD1 activity due to copper deficiency. Because oxidative stress is elevated secondary to decreased SOD1 activity, hsp 32 is induced as another protective mechanism.
authors: Division of Neuropathology, Department of Pathology, School of Medicine, Tottori University Faculty of Medicine, Yonago, 683-8503, Japan ; †Division of Child Neurology, Department of Brain and Neurosciences, School of Medicine, Tottori University Faculty of Medicine, Yonago, 683-8503, Japan.
authors: Atsushi
authors: A
authors: Yokoyama
authors: †Division of Child Neurology, Department of Brain and Neurosciences, School of Medicine, Tottori University Faculty of Medicine, Yonago, 683-8503, Japan ; ‡Sanin Rosai Hospital, Yonago, 683-8605, Japan.
authors: Kousaku
authors: K
authors: Ohno
authors: §Division of Neuropathology, Department of Pathology, Montefiore Medical Center, Albert Einstein College of Medicine, Bronx, New York, USA.
authors: Asao
authors: A
authors: Hirano
authors: ‖Department of Pathology, Osaka Red Cross Hospital, Osaka 543-8555, Japan.
authors: Masayuki
authors: M
authors: Shintaku
authors: ¶Division of Molecular Pathology, Department of Pathology, School of Medicine, Tottori University Faculty of Medicine, Yonago, 683-8503, Japan.
authors: Masako
authors: M
authors: Kato
authors: ¶Division of Molecular Pathology, Department of Pathology, School of Medicine, Tottori University Faculty of Medicine, Yonago, 683-8503, Japan.
authors: Kazuhiko
authors: K
authors: Hayashi
authors: Division of Neuropathology, Department of Pathology, School of Medicine, Tottori University Faculty of Medicine, Yonago, 683-8503, Japan.
authors: Shinsuke
authors: S
authors: Kato
keywords: Menkes kinky hair disease; Purkinje cell; copper chaperone for superoxide dismutase; cytosolic Cu/Zn-superoxide dismutase; immunohistochemistry