Peroxisomal disorders (PDs) are a heterogeneous group of diseases caused by defects in peroxisome biogenesis or functions. X-linked adrenoleukodystrophy is the most prevalent form of PDs and results from mutations in the ABCD1 gene, which encodes a transporter mediating the uptake of very long-chain #fattyacids (VLCFAs). The curative approaches for PDs are very limited. Researchers from Wuhan University investigated whether cholesterol accumulation in the lysosomes is a biochemical feature shared by a broad spectrum of PDs – by individually knocking down fifteen PD-associated genes in cultured cells and found ten induced cholesterol accumulations in the lysosome. 2-Hydroxypropyl-β-#cyclodextrin (HPCD) effectively alleviated the #cholesterol accumulation phenotype in PD-mimicking cells by reducing intracellular cholesterol content as well as promoting cholesterol redistribution to other cellular membranes. In ABCD1 knockdown cells, HPCD treatment lowered reactive oxygen species and VLCFA to normal levels. In Abcd1 knockout mice, HPCD injections reduced cholesterol and VLCFA sequestration in the brain and adrenal cortex. The plasma levels of adrenocortical hormones were increased and the behavioral abnormalities were greatly ameliorated upon HPCD administration. These results suggest that defective cholesterol transport underlies most, if not all, PDs, and that HPCD or potentially other CDs can serve as a novel and effective strategy for the treatment of PDs.

see the full article here: Lysosomal cholesterol accumulation is commonly found in most peroxisomal disorders and reversed by 2-hydroxypropyl-β-cyclodextrin