Baldo Guilherme, Lorenzini Daniel Macedo, Santos Diogenes Santiago, Mayer Fabiana Quoos, Vitry Sandrine, Bigou Stephanie, Heard Jean Michael, Matte Ursula, Giugliani Roberto
Gene Therapy Center, Hospital de Clinicas de Porto Alegre, RS, Brazil.
Research Center in Molecular and Functional Biology, National Institute of Science and Technology on Tuberculosis, Pontifícia Universidade Católica do Rio Grande do Sul, RS, Brazil.
Mol Genet Metab. 2015 Feb;114(2):138-45. doi: 10.1016/j.ymgme.2014.12.301. Epub 2014 Dec 13.
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.
I型黏多糖贮积症（MPS I）是由于α-L-艾杜糖醛酸酶（IDUA）缺乏，导致未降解的糖胺聚糖（GAG）蓄积。该疾病的严重形式表现为病因不明的智力发育迟缓。为了揭示导致MPS I认知障碍的机制，我们研究了MPS I小鼠海马体蛋白质组的变化。8个月大的小鼠表现出溶酶体相关膜蛋白1（LAMP-1）表达增加、神经元和神经胶质细胞中GAG蓄积，以及厌恶和非厌恶记忆受损。我们进行了鸟枪法蛋白质组学分析，鉴定出297种蛋白质。其中32种蛋白质表达存在差异。我们发现组织蛋白酶B和D等蛋白质水平升高；然而它们的增加并未导致MPS I脑内细胞死亡。胶质纤维酸性蛋白（GFAP）明显升高，免疫组织化学证实存在可能导致神经元功能障碍的神经炎症过程。我们未观察到泛素表达以及其他与蛋白质折叠相关的蛋白质存在差异，这表明泛素系统功能正常。最后，我们观察到几种参与突触可塑性的蛋白质发生改变，包括突触后致密蛋白95（PSD95）过表达以及微管相关蛋白1A和1B减少。这些结果共同表明，MPS I小鼠的认知障碍并非由于大量细胞死亡，而是由多种过程导致的神经元功能障碍引起，包括神经炎症和突触可塑性改变。
