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 IduaÀ/À mice. In the present study, we found altered intracellular ionic homeostasis in a different cell type (fibroblasts) from the same murine model. IduaÀ/À 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, IduaÀ/À 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 IduaÀ/À 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-iduronidasedeficient environment provide additional understanding of the clinical multisystemic presentation of this disease and provide new basis for improved therapeutic approaches.

Mucopolysaccharidosis and Autophagy: Controversies on the Contribution of the Process to the Pathogenesis and Possible Therapeutic Applications

“…Contrary to both groups of conclusions mentioned above, normal functions of the autophagy pathway were reported in MPS IIIB (Vitry et al 2010). Accordingly, no alterations in autophagy could be detected in MPS I fibroblasts (Viana et al 2017).…”

Cathepsin B-associated Activation of Amyloidogenic Pathway in Murine Mucopolysaccharidosis Type I Brain Cortex

“…Storage of undegraded lysosomal substrates severely affects the homeostasis of endo-lysosomal pathway leading to increased size and number of lysosomes, as well as variations in their intracellular position, movement, and docking with other vesicles. It also causes changes in the lipid composition and loss of integrity of the lysosomal membrane and alters expression and activity of lysosomal hydrolases in all affected cells and tissues, including the brain [11,13,16,40,[50][51][52][53][54]. Nondividing cells such as brain neurons use autophagy as the main mechanism for clearance of protein aggregates and damaged organelles [55,56].…”

Changes in cellular processes occurring in mucopolysaccharidoses as underestimated pathomechanisms of these diseases

“…In addition, defective autophagy has been suggested in MPS II and VII (Bartolomeo et al, 2017; Fiorenza et al, 2018). Contrary to these reports, articles on autophagy in MPS were published, in which the authors suggested either enhancement of this process in MPS I (Woloszynek et al, 2009; Swaroop et al, 2018) or no changes in MPS IIIB (Vitry et al, 2010) and MPS I (Viana et al, 2017). It has been suggested that such opposing conclusions might arise from different interpretation of experimental results.…”

“…Interestingly, these findings may explain early observations of structural changes in cells of patients suffering from Sanfilippo disease (MPS III) (Haust, 1968). Recently, lower levels of mitochondrial calcium ions and lower mitochondrial membrane potential were described in MPS I mice relative to control animals (Viana et al, 2017). Interestingly, concentrations of calcium ions were higher in the cytoplasm and endoplasmic reticulum in the same MPS I cells.…”