Abstract
The single amino acid mutation G26R in human apolipoprotein A-I (apoA-IIowa) is the first mutation that was associated with familial AApoA1 amyloidosis. The N-terminal fragments (amino acid residues 1–83) of apoA-I containing this mutation deposit as amyloid fibrils in patients’ tissues and organs, but the mechanisms of cellular degradation and cytotoxicity have not yet been clarified. In this study, we demonstrated degradation of apoA-IIowa fibrils via the autophagy-lysosomal pathway in human embryonic kidney 293 cells. ApoA-IIowa fibrils induced an increase in lysosomal pH and the cytosolic release of the toxic lysosomal protease cathepsin B. The mitochondrial dysfunction caused by apoA-IIowa fibrils depended on cathepsin B and was ameliorated by increasing the degradation of apoA-IIowa fibrils. Thus, although apoA-IIowa fibril transport to lysosomes and fibril degradation in lysosomes may have occurred, the presence of an excess number of apoA-IIowa fibrils, more than the lysosomes could degrade, may be detrimental to cells. Our results thus provide evidence that the target of apoA-IIowa fibrils is lysosomes, and we thereby gained a novel insight into the mechanism of AApoA1 amyloidosis.
Highlights
Apolipoprotein A-I, the major protein in high-density lipoproteins, plays a critical role in lipid metabolism by transporting excess cellular cholesterol from the peripheral tissues to the liver[1]
Amyloid fibrils of WT Apolipoprotein A-I (apoA-I) are reportedly associated with atherosclerotic plaques[27], not with hereditary AApoA1 amyloidosis
Because previous reports showed that Aβwas degraded by lysosomes[28,29], we analyzed the effect of chloroquine on cellular degradation of apoA-IIowa fibrils
Summary
Apolipoprotein A-I (apoA-I), the major protein in high-density lipoproteins, plays a critical role in lipid metabolism by transporting excess cellular cholesterol from the peripheral tissues to the liver[1]. A G26R single substitution ( referred to as the Iowa mutation), is the first mutation that was determined to be associated with AApoA1 amyloidosis[7,8] This mutation facilitates proteolysis of apoA-I, and the resulting N-terminal fragments (amino acid residues 1–83) of the variant apoA-I deposit as amyloid fibrils in various organs, such as the kidney, liver, and heart[6,7,9]. We used cell-based assays to investigate the role of lysosomes and autophagy in cellular degradation and cytotoxicity of G26R apoA-I fibrils (apoA-IIowa fibrils). ApoA-IIowa fibrils were degraded via the autophagy-lysosomal pathway in human embryonic kidney (HEK) 293 cells, which resulted in a loss of lysosomal acidity and in the cytosolic release of the lysosomal protease cathepsin B. Our results emphasize the importance of autophagy and lysosomes in the pathology of AApoA1 amyloidosis
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