Researchers Identify Mechanism Involved in Lipid Accumulation in Cells in Niemann-Pick type C1 Disease

Researchers Identify Mechanism Involved in Lipid Accumulation in Cells in Niemann-Pick type C1 Disease

A team of researchers from the University of Barcelona and Barcelona’s August Pi i Sunyer Biomedical Research Institute (IDIBAPS) have identified a mechanism involved in the regulation of cholesterol movement inside cells.

They determined the protein Annexin A6 (AnxA6) plays a vital role in the transport of cholesterol and other lipids inside cells, which could serve as a potential target for treating a range of lysosomal storage disorders such as Niemann–Pick type C1 (NPC1) disease.

NPC1 is a rare progressive disease that is characterized by the inability of the body to transport cholesterol and other lipids inside cells, leading to the accumulation of lipids which causes cell damage. The disease causes lipid accumulation in the cell interior of the endosome. The endosome is important for sorting and delivering internalized material from the cell surface inside cells and from the Golgi to the lysosome.

NPC1 is one of around 50 lysosomal storage disorders. The disease can result in death within just a few weeks, although can develop in adulthood. What is known is the accumulation of lipids in cells in the liver, spleen, brain and nervous tissue causes cell dysfunction and cell death, leading to severe hepatic damage and dementia. There is currently no cure for the disease. It has been estimated to affect around 1 in 100,000 to 1 in 150,000 live births and late onset NPC1 is believed to affect around 1 in 36,000 adults. There are at least 70 genetic mutations that have been identified on the NPC1 gene which account for approximately 95% of all cases of the genetic disease.

Cholesterol is essential for the functioning of cells. It plays a vital role in the organization of membranes and is involved in vesicular trafficking. While there were cellular processes responsible for regulating the movement of cholesterol and other lipids in cells, the mechanism was not well understood.

It is vital to understand how cholesterol and lipid movement inside cells is regulated. “The understanding of these mechanisms is very important to treat diseases in which there is an accumulation of cholesterol and other lipids which cause serious physiological alterations in the liver, spleen and especially the nervous system,” explained the researchers.

The researchers blocked the AnxA6 protein using CRISPR-Cas9 in cells with the NPC1 phenotype, resulting in the release of endosome cholesterol. Further researched showed that silencing the protein resulted in an increase in membrane contact sites (MCS) which stopped the NPC1 mutation effects. Blocking the protein resulted in cholesterol being redirected to other cell compartments and a return to normality.

The discovery of the membrane transport sites involved in cholesterol transport is significant. “We do not know much about the functioning and dynamics of membrane contact sites, but this study goes together with recent ones and shows MCS are a new paradigm for the understanding of the regulation, transport and homeostasis of lipids, cholesterol and calcium,” explained the researchers.

The researchers believe that targeting the protein could prevent the accumulation of cholesterol in NPC1 disease and as many as 12 other diseases, including pancreatic, prostate and breast cancer, in which lipid metabolism plays an important role.

The research is being led by Carles Enrich and Carles Rentero at the University of Barcelona Cell Biology Unit of the Faculty of Medicine and Health Sciences Department of Biochemistry and CELLEX Biomedical Research Center, in collaboration with researchers at the University of Helsinki, University of Sydney, and the Biomedical Research Institute at Hospital Sant Pau in Barcelona.

The research is detailed in the paper – Annexin A6 modulates TBC1D15/Rab7/StARD3 axis to control endosomal cholesterol export in NPC1 cells – which was recently published in the journal Cellular and Molecular Life Sciences. DOI: 10.1007/s00018-019-03330-y

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