title: Altered Cellular Homeostasis in Murine MPS I Fibroblasts: Evidence of Cell-Specific Physiopathology.
abstract: Mucopolysaccharidosis type I (MPS I), a rare autosomal recessive disease, is caused by a deficiency of the lysosomal enzyme alfa-L-iduronidase. Impaired enzyme activity promotes glycosaminoglycans accumulation in several tissues and organs, leading to complex multisystemic complications. Several studies using animal models indicated different intracellular pathways involving MPS I physiopathology; however, the exact mechanisms underlying this syndrome are still not understood. Previous results from our group showed alterations in ionic homeostasis and cell viability of splenocytes and macrophages in Idua-/- mice. In the present study, we found altered intracellular ionic homeostasis in a different cell type (fibroblasts) from the same murine model. Idua-/- fibroblasts from 3-month-old mice presented higher cytoplasmatic and endoplasmic reticulum Ca2+concentration, lower levels of mitochondrial Ca2+and mitochondrial membrane potential and higher cytoplasmatic pH when compared to Idua+/+ animals. Also, Idua-/- fibroblasts were more resistant to the apoptotic induction with staurosporine, indicating a possible resistance to apoptotic induction in those cells. In addition, despite the intracellular ionic imbalance, no significant alterations were found in apoptosis and autophagy in Idua-/- fibroblasts, which implies that the ionic alterations did not activate those pathways. The investigation of mechanisms underlying the cellular physiopathology of lysosomal diseases is crucial for a better understanding about the progression of these diseases. Since splenocytes, macrophages, and fibroblasts have different embryonic origins and distinct structural and functional features, potentially altered signaling pathways found in a cell-specific manner in an alfa-L-iduronidase-deficient environment provide additional understanding of the clinical multisystemic presentation of this disease and provide new basis for improved therapeutic approaches.
authors.affiliation: Department of Pediatrics, Universidade Federal de São Paulo, Rua Napoleão de Barros, 325, 3rd floor, São Paulo, 04024-002, Brazil. gvianabiomed@gmail.com.|Department of Biochemistry, Universidade Federal de São Paulo, São Paulo, Brazil. gvianabiomed@gmail.com.
authors.forename: Gustavo Monteiro
authors.initials: GM
authors.lastname: Viana
authors.affiliation: Department of Psychobiology, Universidade Federal de São Paulo, São Paulo, Brazil.
authors.forename: Cinthia Castro
authors.initials: CC
authors.lastname: do Nascimento
authors.affiliation: Centro Interdisciplinar de Investigação Bioquímica, Universidade de Mogi das Cruzes, Mogi das Cruzes, Brazil.
authors.forename: Edgar Julian
authors.initials: EJ
authors.lastname: Paredes-Gamero
authors.affiliation: Department of Psychobiology, Universidade Federal de São Paulo, São Paulo, Brazil.
authors.forename: Vânia
authors.initials: V
authors.lastname: D'Almeida
keywords: Apoptosis; Autophagy; Calcium; Fibroblasts; Mucopolysaccharidosis type I