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Transforming Proteins May Explain Many Faces of Parkinson’s

We talk about Parkinson’s disease rather than Parkinson’s diseases, as if this disorder was a single thing. It is and it isn’t. Any two patients can differ greatly in when they first showed symptoms, what problems they experience, and how quickly their condition worsens. Some people only ever have difficulties with movement, while others suffer from full-blown dementia.

And yet, every case of Parkinson’s boils down to a protein called alpha-synuclein. Think of a protein as a sculpture made by folding up a long chain of beads. If alpha-synuclein folds correctly, it helps the neurons in our brain to send messages to one another. If it folds incorrectly, it becomes rowdy and sociable, gathering in large destructive clumps that wreck neurons.

How could this common cause lead to such variation in symptoms?

Jing Guo from the University of Pennsylvania School of Medicine has a possible answer. She has shown that alpha-synuclein can actually misfold in two different ways, creating two distinct strains. They’re chemically identical, but subtle differences in their shape imbue them with distinct traits.

Strain A is quick and dirty. When added to neurons, it rapidly produces toxic clumps of alpha-synuclein that kill many cells within a few weeks. Strain B is a slow-burner. It forms clumps more at a more leisurely pace, and didn’t kill any neurons over the course of the experiment.

However, strain B can force another protein called tau to gather into tangled clumps—a hallmark of Alzheimer’s disease. This might explain why these two diseases sometimes show up in the same unfortunate brain. More than half of people with Alzheimer’s have clumps of alpha-synuclein in their brains, while many Parkinson’s patients are riddled with tau tangles.

“These differences in misfolding could account for some of the variation we observe in patients,” says Virginia Lee, who led the study. For example, some people develop their disease at a young age and live with it for a long time, while others only develop symptoms during old age alongside signs of Alzheimer’s. Maybe the former group is afflicted by Strain A, and the latter by Strain B?

The team found some evidence for this by examining the brains of five people who had died with Parkinson’s disease. Chemical tests suggested that the two patients with “pure” Parkinson’s had something that looked like strain A, while three people with a secondary diagnosis of Alzheimer’s had something akin to strain B. It’s hard to draw any firm conclusions from such a small number of people but Patrik Brundin, a Parkinson’s researcher from Lund University, says that the results provide “strong impetus” for more studies that check if these strains exist in real patients and correspond to differences in symptoms.

Other scientists are also impressed. People working in this area have suspected that such strains exist, but Guo’s experiments cement those suspicions. “This paper is a milestone for the field,” says Mathias Jucker from the University of Tübingen, who works on protein diseases like Alzheimer’s. “It’s very impressive, very interesting, very exciting.”

Guo’s team found the two strains by taking mixing isolated alpha-synuclein molecules until they gathered into clumps. They then added these clumps to fresh batches of alpha-synuclein, until these also banded together. After ten rounds of this, they found that the protein morphed into a version that could also nudge tau into clusters—an ability that the first batches lacked. The original Strain A had evolved into a new Strain B.

It’s not clear how this artificial process happens in actual brains, but we can get a big clue by studying prions—the rogue proteins that cause diseases like mad cow disease or Creutzfeld-Jacob disease. Prions also cause disease by folding incorrectly, and they can convert their normal peers into their twisted shapes. They also come in strains that vary in both their shape and their ability to cause disease.

We now know that alpha-synuclein and other proteins behind brain diseases can behave like prions. (I’ve written a lot about this fascinating line of research.) For example, misfolded forms of alpha-synuclein can corrupt normal versions of the same protein. They can travel from neuron to neuron, spreading their dangerous folds through the brain with evangelical fervour.

But the brain is a complicated environment filled with a bustling community of molecules and cells. Perhaps as alpha-synuclein spreads through this changing landscape, it adapts by adopting new shapes and evolving new strains? Maybe a single brain builds up many strains of alpha-synuclein that affect different parts. Maybe we’re starting to understand that Parkinson’s, Alzheimer’s and the like are evolutionary diseases, just as we now realise cancer to be.

Reference: Guo, Covell, Daniels, Iba, Stieber, Zhang, Riddle, Kwong, Xu, Trojanowski & Lee. 2013. Distinct a-Synuclein Strains Differentially Promote tau Inclusions in Neurons. Cell http://dx.doi.org/10.1016/j.cell.2013.05.057

More on misfolded proteins:

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Spreading corrupted proteins cause Parkinson’s signs in mice

This post contains material from an older one, updated based on new discoveries.

There are many things you don’t want gathering in large numbers, including locusts, rioters, and brain proteins. Our nerve cells contain many proteins that typically live in solitude, but occasionally gather in their thousands to form large insoluble clumps. These clumps can be disastrous. They can wreck neurons, preventing them from firing normally and eventually killing them.

Such clumps are the hallmarks of many brain diseases. The neurons of Alzheimer’s patients are riddled with tangles of a protein called tau. Those of Parkinson’s patients contain bundles, or fibrils, of another protein called alpha-synuclein. The fibrils gather into even larger clumps called Lewy bodies.

Now, Virginia Lee from the University of Pennsylvania School of Medicine has confirmed that the alpha-synuclein fibrils can spread through the brains of mice. As they spread, they corrupt local proteins and gather them into fresh Lewy bodies, behaving like gangs that travel from town to town, inciting locals into forming their own angry mobs. And as these mobs spread through the mouse brains, they reproduce two of the classic features of Parkinson’s disease: the death of neurons that produce dopamine, and movement problems.

This is the clearest evidence yet that alpha-synuclein can behave like prions, the proteins that cause mad cow disease, scrapie and Creutzfeld-Jacob disease (CJD). Prions are also misshapen proteins that convert the shape of normal peers. But there is a crucial distinction: prions are infectious. They don’t just spread from cell to cell, but from individual to individual. As far as we know, alpha-synuclein can’t do that.


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Alzheimer’s disease involves the prion-like spread of corrupted proteins

Prions are villains worthy of any comic book. They are infectious misshapen proteins that can convert their normal peers into their own twisted images with a touch. As their numbers grow, they gather in large groups and destroy brain tissue. They cause diseases such as mad cow disease, Creutzfeld-Jacob disease (CJD) and scrapie.

And they’re not alone. It seems that many brain diseases are also caused by clusters of misfolded proteins that can seed fresh groups of themselves. The list includes Alzheimer’s, Parkinson’s and Lou Gehrig’s diseases. None of these are infectious – the proteins behind them can’t spread from one individual to another, but there is mounting evidence that they can trigger waves of corrupted shapes within a single brain.

I wrote about the latest such evidence in Alzheimer’s disease for The Scientist. Here’s a taster. Head over there for more.


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Prions enter stealth mode in the spleen, causing silent infections

There’s something unfeasibly sinister about prions. These infectious entities are incredibly simple, but they can cause fatal and untreatable diseases like mad cow disease, CJD, and others. Prions are malformed versions of a protein called PrP. Like all other proteins, they’re made of chains of amino acids that fold into complex shapes. Prions fold incorrectly, and they encourage normal PrP to do so. These deformed proteins gather in large clumps that wreck brain tissue. Once this process begins, we have no way of stopping it. Prions are little more than bits of renegade origami, but they can bring down that most complex of biological structures – your brain.

It gets worse.

Before they spread to the brain, prions often multiply in the lymphatic systemthe group of organs that includes the spleen, lymph nodes, appendix and tonsils. Vincent Béringue from the French National Institute for Agricultural Research has found that prions can hide in these tissues, turning individuals into silent carriers even if they never actually develop disease. Worse still, the spleen provides an easy entry-point for prions, allowing them to jump more easily from one species to another.