Shotgun proteomics reveals possible mechanisms for cognitive impairment in Mucopolysaccharidosis I mice

被引:18
|
作者
Baldo, Guilherme [1 ]
Lorenzini, Daniel Macedo [2 ]
Santos, Diogenes Santiago [2 ]
Mayer, Fabiana Quoos [1 ]
Vitry, Sandrine [3 ]
Bigou, Stephanie [3 ]
Heard, Jean Michael [3 ]
Matte, Ursula [1 ,4 ]
Giugliani, Roberto [1 ,4 ]
机构
[1] Hosp Clin Porto Alegre, Gene Therapy Ctr, Porto Alegre, RS, Brazil
[2] Pontificia Univ Catolica Rio Grande do Sul, Natl Inst Sci & Technol TB, Res Ctr Mol & Funct Biol, Rio Grande do Sul, RS, Brazil
[3] Inst Pasteur, Dept Neurosci, Retrovirus & Genet Transfer Unit, Paris, France
[4] Univ Fed Rio Grande do Sul, Post Grad Program Genet & Mol Biol, BR-90046900 Porto Alegre, RS, Brazil
关键词
Mucopolysaccharidosis type I; Hurler syndrome; Brain disease; Cathepsin; Ubiquitin; Glial fibrillary acidic protein; STATISTICAL-MODEL; GENE-EXPRESSION; MURINE MODEL; PSD-95; PATHOGENESIS; THERAPY; DISEASE; ORGANS; ONSET; BIRTH;
D O I
10.1016/j.ymgme.2014.12.301
中图分类号
R5 [内科学];
学科分类号
1002 ; 100201 ;
摘要
Mucopolysaccharidosis type I (MPS I) is due to deficient alpha-L-iduronidase (IDUA) which leads to storage of undegraded glycosaminoglycans (GAG). The severe form of the disease is characterized by mental retardation of unknown etiology. Trying to unveil the mechanisms that lead to cognitive impairment in MPS I, we studied alterations in the proteome from MPS I mouse hippocampus. Eight-month old mice presented increased LAMP-1 expression, GAG storage in neurons and glial cells, and impaired aversive and non-aversive memory. Shotgun proteomics was performed and 297 proteins were identified. Of those, 32 were differentially expressed. We found elevation in proteins such as cathepsins B and D; however their increase did not lead to cell death in MPS I brains. Glial fibrillary acid protein (GFAP) was markedly elevated, and immunohistochemistry confirmed a neuroinflammatory process that could be responsible for neuronal dysfunction. We didn't observe any differences in ubiquitin expression, as well as in other proteins related to protein folding, suggesting that the ubiquitin system is working properly. Finally, we observed alterations in several proteins involved in synaptic plasticity, including overexpression of post synaptic density-95 (PSD95) and reduction of microtubule-associated proteins 1A and 1B. These results together suggest that the cognitive impairment in MPS I mice is not due to massive cell death, but rather to neuronal dysfunction caused by multiple processes, including neuroinflammation and alterations in synaptic plasticity. (C) 2015 Elsevier Inc. All rights reserved.
引用
收藏
页码:138 / 145
页数:8
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