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, Laura Volpicelli-Daley from the University of Pennsylvania School of Medicine has confirmed that the alpha-synuclein fibrils can spread. Once they’ve entered a new neuron, they can corrupt the local proteins, changing their shape and gathering them into fresh Lewy bodies. They’re like gangs that travel from town to town, inciting the locals into forming their own angry mobs.
This makes alpha-synuclein a bit like prions, the proteins that cause mad cow disease, scrapie and Creutzfeld-Jacob disease (CJD). Prions are also misshapen proteins that can convert the shape of their 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. Alpha-synuclein can’t do that. “There is no evidence that Parkinson’s disease or other [diseases related to synuclein] can spread from person to person or from animal to person,” says Virginia Lee, who led the study.
Parkinson’s may be confined to a single brain, but it can spread from one part to another. Thanks to studies like these, we know more about how this happens. “This is an outstanding study,” says Patrik Brundin, who works on Parkinson’s disease at Lund University. “It adds to the string of evidence that prion-like mechanisms play an important role in the development of Parkinson’s disease.”
Others studies have suggested that alpha-synuclein fibrils can seed new clumps of diseases proteins in healthy cells. In 2008, two teams showed that normal fetal neurons develop Lewy bodies if they’re transplanted into the brains of a Parkinson’s patient. A year later, other groups showed that if you can shunt alpha-synuclein fibrils into new cells, they create more fibrils.
But all of these studies either forced the fibrils in, used massive concentrations of them, or exposed neurons to the fibrils amid a cocktail of other chemicals. Volpicelli-Daley wanted to see if the fibrils can spread their corruption under natural conditions that better mimic the brains of Parkinson’s patients.
They could. Neurons will happily absorb alpha-synuclein fibrils at normal concentrations. Once inside, they start gathering the local synuclein proteins into fibrils along the stem of the neuron. After a few days, the fibrils move into the heart of the cell, where they create Lewy bodies (note the spread of the green dye in the image above). The cell fails, and eventually dies. “We never expect that it worked so well,” says Lee.
“I like the paper very much,” says Eliezer Masliah, who studies rogue proteins in Alzheimer’s disease. However, he points out that alpha-synuclein fibrils aren’t normally found in the space between cells, so it’s not clear if neurons would have any fibrils to absorb in real life. “There is a question of physiological relevance,” he says, “but it’s possible that very small fragments of fibrils might be released from dying neurons.”
It’s valuable to get clues about how synuclein fibrils spread, but Vopicelli-Daley has done something far more important – she has developed an easy system for studying that spread in the lab. Her experimental set-up is easy to run at a large scale. She’s now in a good position to look at why neurons absorb the fibrils (no one knows), how the Lewy bodies form, how they kill neurons, and how different Parkinson’s genes influence these events. She can also scan large libraries of chemicals to search for drugs that can stop the spread of synuclein.
More broadly, Vopicelli-Daley’s study supports the idea that the spread of rogue proteins is a unifying feature of many brain diseases. Clusters of misfolded Tau and amyloid beta – proteins involved in Alzheimer’s – can instigate fresh clusters in new cells. And as I’ve written about before, a twisted version of SOD1, which causes Lou Gehrig’s disease, can travel from cell to cell and nudge normal proteins into adopting its malformed shape. All these varied diseases could be caused by molecular evangelism gone wrong.
Reference: Volpcelli-Daley, Luk, Patel, Tanik, Riddle, Stieber, Meaney, Trojanowski & Lee. 2011. Exogenous a-Synuclein Fibrils Induce Lewy Body Pathology Leading to Synaptic Dysfunction and Neuron Death. Neuron http://dx.doi.org/10.1016/j.neuron.2011.08.033
More on neural diseases:
- Fishing expedition reveals unexpected link between Alzheimer’s and prion diseases
- Neurons ravaged by infectious mutant sod
- Evolution without genes – prions can evolve and adapt too