Mutational and oxidative stress analysis in patients with mucopolysaccharidosis type I undergoing enzyme replacement therapy

Pereira, Vanessa Gonçalves; Martins, Ana María; Micheletti, Cecília; D’Almeida, Vânia

doi:10.1016/j.cca.2007.09.008

Cited by 52 publications

(45 citation statements)

References 27 publications

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“…In a study using MPS VI rats, it was described a higher expression of cytochrome b5588, involved in oxidative burst of phagocytes (Simonaro et al 2008). Our group have also found evidences of oxidative stress in blood cells from MPS I patients, where increased toxic products from lipid peroxidation, as malondialdehyde, led to lysosomal destabilization and consequently permeabilization (Pereira et al 2008). Evidences of multi-organellar Ca 2+ storage, intracellular pH alterations, and lysosomal permeability with higher cysteine proteases activity and apoptotic rate in murine IduaÀ/À splenocytes were also shown (Pereira et al 2010).…”

Section: Introductionsupporting

confidence: 51%

Altered Cellular Homeostasis in Murine MPS I Fibroblasts: Evidence of Cell-Specific Physiopathology

et al. 2017

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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.

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Section: Introductionsupporting

confidence: 51%

Altered Cellular Homeostasis in Murine MPS I Fibroblasts: Evidence of Cell-Specific Physiopathology

et al. 2017

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“…226 The presence of two nonsense mutations is predictive of a MPS I-H, 226 although one 20-year-old homozygous p.W402X patient was described as having MPS I-S without further description of her phenotype. 227 The p.R89Q missense and the c.678-7gϾa (IVS5-7gϾa) splice site mutations predict a mild phenotype. 228 -232 All three subtypes of MPS I have been reported in patients with the homozygous p.P533R mutation; both MPS I-H and MPS I-HS have been reported with p.P533R compound heterozygotes with other "severe" mutations.…”

Section: Current Diagnosticsmentioning

confidence: 99%

Lysosomal storage diseases: Diagnostic confirmation and management of presymptomatic individuals

Wang

Bodamer

Watson

et al. 2011

Genetics in Medicine

207

242

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“…TBARS and GSH levels were increased when compared to reference levels (Pereira et al 2008). The authors suggest that as erythrocytes can absorb hydrogen peroxide from other cells (Halliwell and Gutteridge 1999) the alterations observed might be caused by increased production of hydrogen peroxide from different tissues.…”

Section: Discussionmentioning

confidence: 90%

Alterations in Oxidative Markers in the Cerebellum and Peripheral Organs in MPS I Mice

Reolon

Reinke²,

Oliveira

et al. 2008

Cell Mol Neurobiol

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Mucopolysaccharidosis type I is a lysosomal storage disease with alterations in several organs. Little is known about the pathways that lead to the pathology. Evidences point oxidative stress on lysosomal storage diseases and mucopolysaccharidosis type I. The aim of the present study was to evaluate oxidative biomarkers on mucopolysaccharidosis type I mice model. We evaluated antioxidant enzymatic activity, protein damage and lipid peroxidation in the forebrain, cerebellum, heart, lung, diaphragm, liver, kidney and spleen. Superoxide dismutase activity was increased on cerebellum, lung, diaphragm, liver and kidney of mucopolysaccharidosis type I mice. Catalase activity was increased on cerebellum, spleen and lung. There was no alteration on glutathione peroxidase activity on any of the analyzed organs. Mucopolysaccharidosis type I mice showed increased carbonyl groups on cerebellum, heart and spleen. There was a decrease of thiobarbituric acid-reactive substances on the cerebellum of mucopolysaccharidosis type I mice. The results indicate a oxidative imbalance in this model. As lysosomes are very susceptible to oxidative damage, leading inclusive to cellular death, and lysosomal storage diseases present several alterations on this organelles, this finding can help to elucidate the cellular damage pathways on mucopolysaccharidosis type I.

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Mutational and oxidative stress analysis in patients with mucopolysaccharidosis type I undergoing enzyme replacement therapy

Cited by 52 publications

References 27 publications

Altered Cellular Homeostasis in Murine MPS I Fibroblasts: Evidence of Cell-Specific Physiopathology

Altered Cellular Homeostasis in Murine MPS I Fibroblasts: Evidence of Cell-Specific Physiopathology

Lysosomal storage diseases: Diagnostic confirmation and management of presymptomatic individuals

Alterations in Oxidative Markers in the Cerebellum and Peripheral Organs in MPS I Mice

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