Arginine improves peroxisome functioning in cells from patients with a mild peroxisome biogenesis disorder

Abstract

BackgroundZellweger spectrum disorders (ZSDs) are multisystem genetic disorders caused by a lack of functional peroxisomes, due to mutations in one of the PEX genes, encoding proteins involved in peroxisome biogenesis. The phenotypic spectrum of ZSDs ranges from an early lethal form to much milder presentations. In cultured skin fibroblasts from mildly affected patients, peroxisome biogenesis can be partially impaired which results in a mosaic catalase immunofluorescence pattern. This peroxisomal mosaicism has been described for specific missense mutations in various PEX genes. In cell lines displaying peroxisomal mosaicism, peroxisome biogenesis can be improved when these are cultured at 30°C. This suggests that these missense mutations affect the folding and/or stability of the encoded protein. We have studied if the function of mutant PEX1, PEX6 and PEX12 can be improved by promoting protein folding using the chemical chaperone arginine.MethodsFibroblasts from three PEX1 patients, one PEX6 and one PEX12 patient were cultured in the presence of different concentrations of arginine. To determine the effect on peroxisome biogenesis we studied the following parameters: number of peroxisome-positive cells, levels of PEX1 protein and processed thiolase, and the capacity to β-oxidize very long chain fatty acids and pristanic acid.ResultsPeroxisome biogenesis and function in fibroblasts with mild missense mutations in PEX1, 6 and 12 can be improved by arginine.ConclusionArginine may be an interesting compound to promote peroxisome function in patients with a mild peroxisome biogenesis disorder.

Fatty acid oxidation flux predicts the clinical severity of VLCAD deficiency

“…The use of chemical chaperones for VLCAD might therefore have a beneficial effect by stabilizing the mutant protein and enhance protein folding at 37 °C. 31 Our data suggest that functional assays in fibroblasts are better predictors of clinical severity than specific genotypes. Missense mutations often cause variable clinical phenotypes.…”

Arginine Functionally Improves Clinically Relevant Human Galactose-1-Phosphate Uridylyltransferase (GALT) Variants Expressed in a Prokaryotic Model

“…A positive role of arginine has also been observed in the peroxisome function of cultured cells from peroxisome biogenesis disorder patients with mutations in PEX1, PEX6, and PEX12 (Berendse et al 2013). Furthermore, arginine is a long-recognized protein stabilizer that has been proposed to exert an anti-aggregation effect by increasing the activation energy of protein aggregation (Baynes et al 2005).…”

A Thermolabile Aldolase A Mutant Causes Fever-Induced Recurrent Rhabdomyolysis without Hemolytic Anemia

“…Also, they develop a system of defenses that represent an excellent example of redox balance maintenance [24]. Interestingly, we showed that protein and catalytic breakdown can be reversed by arginine but not by glycerol, benzylhydantoin and betaine which all might act as a chaperone as recently proposed for unrelated metabolic disorders [25]–[27]. Also, another mechanism may be proposed concerning the effective role of L-arginine on aldolase A activity, namely its antioxidant function via increased NO formation and reduced release of superoxide.…”

“…Three other chaperons (sigma) were also tested, glycerol (100 mM) [25] for 10 days, betaine (10 and 50 mM) [26], [27] and benzylhydantoin (130 µM) for 3 days. Uniformly stable isotope labeled (U- 13 C 5 ) glutamine or (U- 13 C 6 ) arginine (Eurisotop, Saint-Aubin, France) were provided to myoblasts (1 mM) in the presence of glucose (2.5 mM) and incubated without serum for 6 hours.…”