Neuropathology provides clues to the pathophysiology of Gaucher disease

被引:345
作者
Wong, KD
Sidransky, E
Verma, A
Mixon, TH
Sandberg, GD
Wakefield, LK
Morrison, A
Lwin, A
Colegial, C
Allman, JM
Schiffmann, R [1 ]
机构
[1] Armed Forces Inst Pathol, Dept Neuropathol, Washington, DC 20306 USA
[2] NHGRI, Sect Mol Neurogenet, NIMH, NIH, Bethesda, MD 20892 USA
[3] NHGRI, Sect Mol Neurogenet, Med Genet Branch, NIH, Bethesda, MD 20892 USA
[4] Uniformed Serv Univ Hlth Sci, Dept Neurol, Bethesda, MD 20814 USA
[5] CALTECH, Integrat Biol Sect, Div Biol, NIH,NINDS, Bethesda, MD USA
[6] NINDS, Dev & Metab Neurol Branch, NIH, Bethesda, MD 20892 USA
关键词
Gaucher disease; hippocampus; glucocerebrosidase; calcarine cortex; astrogliosis; neuronal loss; synuclein; Lewy body; Parkinsonism;
D O I
10.1016/j.ymgme.2004.04.011
中图分类号
R5 [内科学];
学科分类号
1002 ; 100201 ;
摘要
To better understand the pathogenesis of brain dysfunction in Gaucher disease (GD), we studied brain pathology in seven subjects with type 1 GD (four also exhibited parkinsonism and dementia), three with type 2 GD and four with type 3 GD. Unique pathologic patterns of disease involving the hippocampal CA2-4 regions and layer 4b of the calcarine cortex were identified. While these findings were common to all three GD phenotypes, the extent of the changes varied depending on the severity of disease. Cerebral cortical layers 3 and 5, hippocampal CA2-4, and layer 4b were involved in all GD patients. Neuronal loss predominated in both type 2 and type 3 patients with progressive myoclonic encephalopathy, whereas patients classified as type 1 GD had only astrogliosis. Adjacent regions and lamina, including hippocampal CA1 and calcarine lamina 4a and 4c were spared of pathology, highlighting the specificity of the vulnerability of selective neurons. Elevated glucocerebrosidase expression by immunohistochemistry was found in CA2-4. Hippocampal Ca-45(2+) uptake autoradiography in rat brain was performed demonstrating that hippocampal CA2-4 neurons, rather than CA1 neurons, were calcium-induced calcium release sensitive (CICR-sensitive). These findings match recent biochemical studies linking elevated glucosylceramide levels to sensitization of CA2-4 RyaR receptors and 300% potentiation of neuronal CICR sensitivity. In two patients with type 1 GD and parkinsonism, numerous synuclein positive inclusions, similar to brainstem-type Lewy bodies found in Parkinson disease, were also found hippocampal CA2-4 neurons. These findings argue for a common cytotoxic mechanism linking aberrant glucocerebrosidase activity, neuronal cytotoxicity, and cytotoxic Lewy body formation in GD. Published by Elsevier Inc.
引用
收藏
页码:192 / 207
页数:16
相关论文
共 89 条
[1]  
ADACHI M, 1967, ARCH PATHOL, V83, P513
[2]  
Allman J, 1988, VISUAL CORTEX PRIMAT, P279
[3]  
Amaral D G, 1991, Hippocampus, V1, P415, DOI 10.1002/hipo.450010410
[4]  
Banker BQ, 1962, CEREBRAL SPHINGOLIPI, P73
[5]   MONOCLONAL-ANTIBODIES AGAINST HUMAN BETA-GLUCOCEREBROSIDASE [J].
BARNEVELD, RA ;
TEGELAERS, FPW ;
GINNS, EI ;
VISSER, P ;
LAANEN, EA ;
BRADY, RO ;
GALJAARD, H ;
BARRANGER, JA ;
REUSER, AJJ ;
TAGER, JM .
EUROPEAN JOURNAL OF BIOCHEMISTRY, 1983, 134 (03) :585-589
[6]  
Beutler E., 2001, METABOLIC MOL BASES, V3, P3635
[7]   Phosphatidylcholine synthesis is elevated in neuronal models of Gaucher disease due to direct activation of CTP:phosphocholine cytidylyltransferase by glucosylceramide [J].
Bodennec, J ;
Pelled, D ;
Riebeling, C ;
Trajkovic, S ;
Futerman, AH .
FASEB JOURNAL, 2002, 16 (13) :1814-+
[8]  
Brady R. O., 1983, METABOLIC BASIS INHE, P842
[9]   DEMONSTRATION OF A DEFICIENCY OF GLUCOCEREBROSIDE-CLEAVING ENZYME IN GAUCHERS DISEASE [J].
BRADY, RO ;
KANFER, JN ;
BRADLEY, RM ;
SHAPIRO, D .
JOURNAL OF CLINICAL INVESTIGATION, 1966, 45 (07) :1112-&
[10]   SPHINGOLIPIDOSES [J].
BRADY, RO .
ANNUAL REVIEW OF BIOCHEMISTRY, 1978, 47 :687-713