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:
- Spreading corrupted proteins cause Parkinson’s signs in mice
- Clumps of rogue Parkinson’s proteins spread to new neurons and seed more clumps
- Alzheimer’s disease involves the prion-like spread of corrupted proteins
- Neurons ravaged by infectious mutant sod
- Prions enter stealth mode in the spleen, causing silent infections
- Evolution without genes – prions can evolve and adapt too
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