Abstract
Peroxisome biogenesis disorders within the Zellweger spectrum (PBD-ZSDs) are most frequently associated with the c.2528G>A (p.G843D) mutation in the PEX1 gene (PEX1-G843D), which results in impaired import of peroxisomal matrix proteins and, consequently, defective peroxisomal functions. A recent study suggested that treatment with autophagy inhibitors, in particular hydroxychloroquine, would be a potential therapeutic option for PBD-ZSD patients carrying the PEX1-G843D mutation. Here, we studied whether autophagy inhibition by chloroquine, hydroxychloroquine and 3-methyladenine indeed can improve peroxisomal functions in four different cell types with the PEX1-G843D mutation, including primary patient cells. Furthermore, we studied whether autophagy inhibition may be the mechanism underlying the previously reported improvement of peroxisomal functions by L-arginine in PEX1-G843D cells. In contrast to L-arginine, we observed no improvement but a worsening of peroxisomal metabolic functions and peroxisomal matrix protein import by the autophagy inhibitors, while genetic knock-down of ATG5 and NBR1 in primary patient cells resulted in only a minimal improvement. Our results do not support the use of autophagy inhibitors as potential treatment for PBD-ZSD patients, whereas L-arginine remains a therapeutically promising compound.
Highlights
The Peroxisome Biogenesis Disorders (PBDs), which include the Zellweger spectrum disorders (PBD-ZSDs) and Rhizomelic Chondrodysplasia Punctata type 1, comprise a group of autosomal recessive metabolic disorders associated with multi-organ defects due to the loss of functional peroxisomes (Klouwer et al, 2015; Braverman et al, 2016)
In contrast to L-arginine, which markedly improved peroxisomal functions, we found that the autophagy inhibitors did not improve endogenous peroxisomal matrix protein import or peroxisomal metabolic functions, but caused a further decrease of the peroxisomal functions in all cell lines, including the primary patient cells
We previously showed that L-arginine improves peroxisomal matrix protein import and peroxisomal metabolic functions in cultured primary skin fibroblasts derived from PEX1-G843D patients (Berendse et al, 2013)
Summary
The Peroxisome Biogenesis Disorders (PBDs), which include the Zellweger spectrum disorders (PBD-ZSDs) and Rhizomelic Chondrodysplasia Punctata type 1, comprise a group of autosomal recessive metabolic disorders associated with multi-organ defects due to the loss of functional peroxisomes (Klouwer et al, 2015; Braverman et al, 2016). Peroxisomes are single-membrane-bound organelles present in virtually every human cell and involved in several crucial metabolic processes. These include, among others, Autophagy Inhibition and Peroxisomal Functions the α- and β-oxidation of branched-chain and very long chain fatty acids (VLCFAs), the synthesis of bile acids and ether phospholipids, including plasmalogens, and the homeostasis of reactive oxygen species (Wanders and Waterham, 2006). Defects in any of these PEX proteins result in a defective peroxisome biogenesis (assembly), which affects peroxisome-dependent metabolic processes This results in characteristic metabolic aberrations reflecting peroxisomal dysfunction, including increased levels of VLCFAs, such as C26:0, pristanic acid and bile acid precursors, and decreased levels of plasmalogens, mature bile acids and docosahexaenoic acid (DHA) (Wanders and Waterham, 2006; Waterham et al, 2016)
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