TY - JOUR
T1 - Autophagy Inhibitors Do Not Restore Peroxisomal Functions in Cells With the Most Common Peroxisome Biogenesis Defect
AU - Klouwer, Femke C. C.
AU - Falkenberg, Kim D.
AU - Ofman, Rob
AU - Koster, Janet
AU - van Gent, D. mi
AU - Ferdinandusse, Sacha
AU - Wanders, Ronald J. A.
AU - Waterham, Hans R.
N1 - Funding Information: We thank Henny Rusch, Petra Mooyer, and Martin Vervaart for technical assistance, and Nancy Braverman from the McGill University Health Centre in Montreal for providing the transformed/immortalized PEX1-G843D and the PEX1-G843D+GFP-PTS1 fibroblast cell lines. Funding. This study was supported by grants from Hersenstichting (F 2012(1)-102), the Marie Curie Initial Training Networks action (FP7-2012-PERFUME-316723), and E-Rare-3 PERescue (ZonMW # 9003037605). Publisher Copyright: © Copyright © 2021 Klouwer, Falkenberg, Ofman, Koster, van Gent, Ferdinandusse, Wanders and Waterham.
PY - 2021/4/1
Y1 - 2021/4/1
N2 - 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.
AB - 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.
KW - L-arginine
KW - Zellweger spectrum disorder
KW - autophagy inhibitors
KW - chloroquine
KW - hydroxychloroquine
KW - peroxisomal functions
KW - peroxisome biogenesis disorder
KW - pexophagy
UR - http://www.scopus.com/inward/record.url?scp=85104236110&partnerID=8YFLogxK
U2 - https://doi.org/10.3389/fcell.2021.661298
DO - https://doi.org/10.3389/fcell.2021.661298
M3 - Article
C2 - 33869228
SN - 2296-634X
VL - 9
JO - Frontiers in cell and developmental biology
JF - Frontiers in cell and developmental biology
M1 - 661298
ER -