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Neuropathology provides clues to the pathophysiology of Gaucher disease

Wong, Kondi and Sidransky, Ellen and Verma, Ajay and Mixon, Tonghui and Sandberg, Glenn D. and Wakefield, Laura K. and Morrison, Alan and Lwin, Alicia and Colegial, Carlos and Allman, John M. and Schiffmann, Raphael (2004) Neuropathology provides clues to the pathophysiology of Gaucher disease. Molecular Genetics and Metabolism, 82 (3). pp. 192-207. ISSN 1096-7192. doi:10.1016/j.ymgme.2004.04.011.

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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 ⁴⁵Ca²⁺ 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.

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Additional Information:© 2004 Published by Elsevier Inc. Received 2 March 2004, Revised 17 April 2004, Accepted 26 April 2004, Available online 9 June 2004.
Subject Keywords:Gaucher disease; Hippocampus; Glucocerebrosidase; Calcarine cortex; Astrogliosis; Neuronal loss; Synuclein; Lewy body; Parkinsonism
Issue or Number:3
Record Number:CaltechAUTHORS:20200716-152739236
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Official Citation:Kondi Wong, Ellen Sidransky, Ajay Verma, Tonghui Mixon, Glenn D Sandberg, Laura K Wakefield, Alan Morrison, Alicia Lwin, Carlos Colegial, John M Allman, Raphael Schiffmann, Neuropathology provides clues to the pathophysiology of Gaucher disease, Molecular Genetics and Metabolism, Volume 82, Issue 3, 2004, Pages 192-207, ISSN 1096-7192, (
Usage Policy:No commercial reproduction, distribution, display or performance rights in this work are provided.
ID Code:104415
Deposited By: Tony Diaz
Deposited On:17 Jul 2020 00:00
Last Modified:16 Nov 2021 18:31

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