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Researchers overcome cholesterol overload in rare genetic disorder

18 November 2019

Combating cholesterol issues in people with Niemann Pick disease

In a world-first, researchers have discovered the main reason why cholesterol accumulates in people with the rare progressive genetic disease called Niemann Pick Type C1 (NPC1).

Affecting roughly 1:150,000, Niemann Pick disease type C1 (NPC1) is characterised by the inability of the body to transport cholesterol inside of cells. The fatty substance then accumulates, causing liver and nerve damage and eventually a form of dementia.

Associate Professor Thomas Grewal and his team from the University of Sydney School of Pharmacy have discovered a primary reason why cholesterol accumulates in NPC1 patients. The research, published in the top international journal Cellular and Molecular Life Sciences, found a lack of communication between two tiny cellular structures blocking how cholesterol moves inside cells, which is critical for healthy cells.

Senior paper author Associate Professor Grewal has described the research as a major finding in the search to explain why cholesterol overload in one organelle, late endosomes, of NPC1 patients can cause liver disfunction and neurodegeneration.

The research has important implications for inborn errors in metabolism, neurology and is highly relevant for cardiovascular researchers, as NPC1 is at the crossroads of key pathways that determine how the body handles LDL or 'bad' cholesterol.

There is currently no cure for Niemann Pick disease type C1, available treatments focus on reducing cholesterol overload. Miglustat is the only drug available for patients, though severe side effects limit its use.

The study's findings have identified a strongly reduced number of so-called 'membrane contacts' within the cells of affected people. Interestingly, the induction of membrane contacts between these two cell structures which were blocking cholesterol movement for people with NPC1 bypassed the genetic mutation, directing cholesterol out of the cell and returning cells to normal. These findings advance current approaches to overcome cholesterol overload in NPC1 disease and could significantly help to reduce its impact.

The publication in Cellular and Molecular Life Sciences is the culmination of six years of research, which was a collaboration between University of Sydney researchers in Helsinki, Hamburg and Barcelona, as well as PhD students in Associate Professor Grewal's team.

Associate Professor Grewal has been collaborating with Professor Carlos Enrich from the University of Barcelona's Faculty of Medicine on the pathways that determine cholesterol distribution inside cells for two decades.