title: Shotgun proteomics reveals possible mechanisms for cognitive impairment in Mucopolysaccharidosis I mice.
abstract: 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.
authors.affiliation: Gene Therapy Center, Hospital de Clinicas de Porto Alegre, RS, Brazil. Electronic address: gbaldo@hcpa.ufrgs.br.
authors.forename: Guilherme
authors.initials: G
authors.lastname: Baldo
authors.affiliation: 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.
authors.forename: Daniel Macedo
authors.initials: DM
authors.lastname: Lorenzini
authors.affiliation: 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.
authors.forename: Diogenes Santiago
authors.initials: DS
authors.lastname: Santos
authors.affiliation: Gene Therapy Center, Hospital de Clinicas de Porto Alegre, RS, Brazil.
authors.forename: Fabiana Quoos
authors.initials: FQ
authors.lastname: Mayer
authors.affiliation: Retrovirus and Genetic Transfer Unit, Department of Neuroscience, Pasteur Institute, Paris, France.
authors.forename: Sandrine
authors.initials: S
authors.lastname: Vitry
authors.affiliation: Retrovirus and Genetic Transfer Unit, Department of Neuroscience, Pasteur Institute, Paris, France.
authors.forename: Stephanie
authors.initials: S
authors.lastname: Bigou
authors.affiliation: Retrovirus and Genetic Transfer Unit, Department of Neuroscience, Pasteur Institute, Paris, France.
authors.forename: Jean Michael
authors.initials: JM
authors.lastname: Heard
authors.affiliation: Gene Therapy Center, Hospital de Clinicas de Porto Alegre, RS, Brazil; Post Graduation Program in Genetics and Molecular Biology, Universidade Federal do Rio Grande do Sul, RS, Brazil.
authors.forename: Ursula
authors.initials: U
authors.lastname: Matte
authors.affiliation: Gene Therapy Center, Hospital de Clinicas de Porto Alegre, RS, Brazil; Post Graduation Program in Genetics and Molecular Biology, Universidade Federal do Rio Grande do Sul, RS, Brazil.
authors.forename: Roberto
authors.initials: R
authors.lastname: Giugliani
mesh_terms: D000818:Animals; D001921:Brain / Q000503:physiopathology; D002401:Cathepsin B / Q000378:metabolism; D002402:Cathepsin D / Q000378:metabolism / Q000494:pharmacology; D003071:Cognition; D003072:Cognition Disorders / Q000209:etiology*; D004195:Disease Models, Animal; D005904:Glial Fibrillary Acidic Protein / Q000378:metabolism; D006025:Glycosaminoglycans / Q000378:metabolism; D006624:Hippocampus / Q000378:metabolism* / Q000503:physiopathology; D007068:Iduronidase / Q000172:deficiency; D051907:Lysosomal Membrane Proteins / Q000235:genetics / Q000378:metabolism; D051379:Mice; D008059:Mucopolysaccharidosis I / Q000150:complications* / Q000378:metabolism* / Q000503:physiopathology; D009457:Neuroglia / Q000378:metabolism; D009474:Neurons / Q000378:metabolism; D020543:Proteome / Q000032:analysis*; D040901:Proteomics; D052118:Lysosomal-Associated Membrane Protein 1
chemical_list: D002401:Cathepsin B; D002402:Cathepsin D; D005904:Glial Fibrillary Acidic Protein; D006025:Glycosaminoglycans; D007068:Iduronidase; D051907:Lysosomal Membrane Proteins; D020543:Proteome; C052255:Lamp1 protein, mouse; D052118:Lysosomal-Associated Membrane Protein 1
keywords: Brain disease; Cathepsin; Glial fibrillary acidic protein; Hurler syndrome; Mucopolysaccharidosis type I; Ubiquitin