Growing evidence suggests that structurally different aggregates of misfolded protein may underlie some of the bewildering heterogeneity with which neurodegenerative diseases express themselves in patients. In the June 10 Nature online, researchers led by Ronald Melki at the French National Center for Scientific Research, Gif–sur–Yvette, France, and Veerle Baekelandt at KU Leuven, Belgium, make a case that this is true in synucleinopathies. They report that injecting different types of α-synuclein aggregate into rat brains resulted in distinct pathologic consequences. Flat, ribbon-like aggregates gave rise to Lewy bodies and glial inclusions similar to those seen in multiple-system atrophy, while cylindrical fibrils triggered the degeneration of dopaminergic neurons and motor problems like those that bedevil Parkinson’s patients. “The structural differences [of aggregates] define their propensity to target different cells and circuits within our brains,” Melki wrote to Alzforum.
“These results suggest that different synucleinopathies are defined by different strains of α-synuclein aggregate,” wrote Seung-Jae Lee at Seoul National University College of Medicine and Eliezer Masliah at the University of California, San Diego, in an accompanying News & Views commentary.
Several studies support the existence of distinct strains of misfolded protein, which then propagate themselves through the brain by seeding (see Apr 2015 conference news). So far, little is known about how such strains might affect pathology and behavior. Researchers at the University of Minnesota, Minneapolis, recently reported that two different structural classes of Aβ oligomer produced distinct effects in vivo, and different strains of both Aβ and tau have been found in human tissue (see Jun 2015 news; Sep 2013 news; May 2014 news). For α-synuclein, researchers reported that certain aggregate structures can seed tau tangles, while others drive α-synuclein deposits (see Jul 2013 news). Melki had previously distinguished between two classes of α-synuclein aggregate, ribbons and fibrils. In cell cultures, fibrils were more toxic and seeded longer-lasting aggregates than ribbons (see Bousset et al., 2013).
Ribbons Seed Pathology. In rats injected with α-synuclein ribbons, characteristic α-synuclein deposits (red) form in dopaminergic neurons (left panel), in dopaminergic axons (middle), and in oligodendrocytes (right). [Courtesy of Peelaerts et al., Nature.]
The authors wondered if the two forms might also cause different pathology in the brain. First author Wouter Peelaerts generated oligomers, ribbons, and fibrils from synthetic α-synuclein in vitro using different incubation conditions. The authors then injected 10 μg of each preparation into the substantia nigra of wild-type rats. Over the course of a week, all three assemblies were taken up by dopaminergic neurons, transported anterogradely down axons, and internalized by other neurons. Oligomers dispersed farther through the brain than ribbons or fibrils did. This may be due to their smaller size, Melki suggested.
Four months later, the effects of each kind of aggregate varied widely. Ribbons spurred the formation of Lewy bodies and Lewy neurites in dopaminergic neurons, but had no other ill effects. Fibrils did not seed Lewy bodies, but were associated with a 30 percent loss of dopaminergic neurons, and about a 25 percent loss of motor control in the rats’ forepaws, even in wild-type rats. Surprisingly, oligomers caused no problems in this study, belying previous reports that these forms precipitated the most cellular stress and death (see Nov 2009 conference news; Mar 2012 news).
Would these effects be more severe in a background of α-synuclein overexpression? The scientists injected each type of aggregate into transgenic rats that overexpress wild-type human α-synuclein, lose dopaminergic neurons, and develop motor impairments with age (see Van der Perren et al., 2015). In these animals, the ribbons mildly exacerbated both neurodegeneration and motor phenotype, demonstrating that they can be toxic. Ribbons also produced more Lewy bodies in the transgenics than in wild-type rats, and seeded glial cytoplasmic inclusions in oligodendrocytes as well. Such inclusions are a mark of multiple-system atrophy.
Fibrils again inflicted the largest hit on neurodegeneration, greatly accelerating this process. Among dopaminergic neurons, about half died, nerve terminals in the striatum disappeared, and the rats lost about 75 percent of control in their forepaws. Fibrils seeded sparse Lewy bodies in the transgenic rats. In the synuclein-overexpression model, unlike wild-type, injected oligomers did have an effect, worsening dopamine neuron loss and motor problems.
Overall, the findings highlight that α-synuclein fibrils are the form most toxic to neurons, Melki wrote to Alzforum. He speculated that the data tie fibrils to degeneration and Parkinson’s disease, while ribbons may give rise to multiple-system atrophy. In future work, Melki will examine whether α-synuclein assemblies from the brains of patients with synucleinopathies follow this pattern. To try to learn how each type of aggregate penetrates cells, he will determine the proteins with which they interact. That information could suggest new therapeutic strategies for limiting disease spread, he suggested.
Besides spreading through the brain, could α-synuclein aggregates cross the blood-brain barrier? After injecting each type into the bloodstream of wild-type rats twice weekly over four months, the authors indeed spotted each in their brains. Fibrils accumulated in cortical neurons, spinal cords, and activated microglia.
Kelvin Luk at the University of Pennsylvania, Philadelphia, found the intravenous injection data particularly intriguing. “It suggests there might be ways other than neuron-to-neuron transmission for α-synuclein to disseminate in vivo,” he told Alzforum. Aβ has also been shown to travel from blood to brain to seed amyloidosis (see Oct 2010 news). Overall, Luk called the experiments comprehensive and fascinating, but he noted that researchers still do not know if ribbons and fibrils reflect actual conformations in human disease. A few studies have injected brain material from Parkinson’s or multiple-system atrophy patients into animals and seen pathology, but have not characterized aggregate structures (see Watts et al., 2013; Recasens et al., 2014).
Ole Isacson of Harvard Medical School’s McLean Hospital, Belmont, Massachusetts, was struck by the finding that α-synuclein overexpression alone was more toxic than aggregate injection in these experiments. Several Parkinson’s models employ a similar overexpression approach to trigger disease (see Ulusoy et al., 2010). “This suggests that intracellular, not secreted, accumulation of α-synuclein is the key cell biological driver of pathology in Parkinson’s disease,” he wrote to Alzforum.—Madolyn Bowman Rogers
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- Chicago: Tau and α-Synuclein Oligomers Follow Aβ Footsteps
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- Peripheral Aβ Seeds CAA and Parenchymal Amyloidosis
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- Form and Function: What Makes α-Synuclein Toxic?
- Are Synuclein Seeds Non-Starters?
- Alpha-Synuclein Types Congregate in Presynapse—Which Is the Bad One?
- Tau, α-Synuclein Spread: Crazy Stuff—How Might It Work?
- Toxic Synuclein Corrupts Native in Wild-Type Mice
- Synthetic Synuclein Corrupts Native Along Mouse Brain Networks
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