Links between type 2 diabetes and toxin protein

Researchers at Whitehead Institute is casting new light on the theory that abnormal protein deposits like the ones that emerge in neurodegenerative disorders such as Alzheimer’s disease accumulate in and around beta cells and derail their normal function of a key protein, known as Ste24, which unclogs the cellular machinery that  shuttle proteins into compartments within the cell.

This unclogging action could be an important way to minimize the protein deposits that damage precious beta cells in type 2 diabetes.
Alongside the glucose-lowering hormone insulin, beta cells produce another protein, called IAPP-islet amyloid polypeptide). As these two proteins mature inside the cells, they are bundled together and released within the same miniature packets, or vesicles. IAPP is prone to forming large aggregates which can pile up within and outside of cells. As demand for insulin increases, it leads to more IAPP production. The more the production, the more it will aggregate.

Making more IAPP starts poisoning very cells that are producing it. Researchers pioneering approach leverages the baker’s yeast. Saccharomyces cerevisiae to create models of toxic proteins in order to probe, perturb, and expose their underlying biology. They generated a yeast model that carries six tandem copies of IAPP. With the model of IAPP toxicity, the researchers then turned to genetic techniques to identify yeast proteins that either enhance or ameliorate the effects of IAPP aggregation.

Ste24 can cleave proteins that clog translocons the channels through which secreted proteins, including IAPP, must pass before they can be released. Much like liquid drain cleaners can clear household pipes of hair balls and other muck, Ste24 can remove proteins that get stuck as they venture through the cell’s inner straits. Overexpressing Ste24 in his yeast model can rescue some of the effects of IAPP deposits. Ste24 is highly conserved through evolution, so much so that the human version- ZMPSTE24, can stand in for its yeast counterpart.

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