How disordered proteins spread from cell to cell, potentially spreading disease

One bad apple is all it takes to spoil the barrel. And one misfolded protein may be all that's necessary to corrupt other proteins, forming large aggregations linked to several incurable neurodegenerative diseases such as Huntington's, Parkinson's and Alzheimer's.

Researchers have shown that the mutant, misfolded protein responsible for Huntington's disease can move from cell to cell, recruiting normal proteins and forming aggregations in each cell it visits. Knowing that this protein spends part of its time outside cells opens up the possibility for therapeutics. Kopito studies how such misfolded proteins get across a cell's membrane and into its cytoplasm, where they can interact with normal proteins. They are also investating how these proteins move between neuronal cells. The ability of these proteins to move from one cell to another could explain the way Huntington's disease spreads through the brain after starting in a specific region. Similar mechanisms may be involved in the progress of Parkinson's and Alzheimer's through the brain.

Not all misfolded proteins are bad. The dogma used to be that all our proteins formed neat, well-folded structures, packed together in complexes with a large number of other proteins. But over the past 20 years, researchers have found that as much as 30 percent of our proteins never fold into stable structures. And even ordered proteins appear to have some disordered parts.

Disordered proteins are important for normal cellular functions. Unlike regular proteins, they only interact with one partner at a time. But they are much more dynamic, capable of several quick interactions with many different proteins. This makes them ideal for a lot of the standard communication that happens within a cell for its normal functioning.

But if some of our proteins are always disordered, how do our cells tell which proteins need to be properly folded, and which don't? It's a big mystery.

Huntington's disease is caused by a specific mutated protein. But the body makes this mutant protein all your life, so why do you get the disease in later adulthood? It's because the body's protective mechanisms stop doing their job as we get older.

But it's clear what happens when these mechanisms stop working – misfolded proteins start recruiting normal versions of the same protein and form large aggregations. The presence of these aggregations in neurons has been closely linked with several neurodegenerative diseases.

Researchers found that the mutant protein associated with Huntington's disease can leave one cell and enter another one, stirring up trouble in each new cell as it progresses down the line. The spread of the misfolded protein may explain how Huntington's progresses through the brain.

This disease, like Parkinson's and Alzheimer's, starts in one area of the brain and spreads to the rest of it. This is also similar to the spread of prions, the self-replicating proteins implicated in mad cow disease and, in humans, Creutzfeldt-Jakob disease. As the misfolded protein reaches more parts of the brain, it could be responsible for the progressive worsening of these diseases.

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