Chapter title |
Altered Cellular Homeostasis in Murine MPS I Fibroblasts: Evidence of Cell-Specific Physiopathology
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Chapter number | 5 |
Book title |
JIMD Reports, Volume 36
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Published in |
JIMD Reports, February 2017
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DOI | 10.1007/8904_2017_5 |
Pubmed ID | |
Book ISBNs |
978-3-66-256137-9, 978-3-66-256138-6
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Authors |
Gustavo Monteiro Viana, Cinthia Castro do Nascimento, Edgar Julian Paredes-Gamero, Vânia D’Almeida, Viana, Gustavo Monteiro, do Nascimento, Cinthia Castro, Paredes-Gamero, Edgar Julian, D’Almeida, Vânia |
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 Ca(2+) concentration, lower levels of mitochondrial Ca(2+) 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. |
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