Good Amyloid, Bad Amyloid—What’s the Difference?

Why do some amyloids cause serious neurodegenerative diseases, while others have important biological functions? A new study of the functional amyloid Orb2 suggests that it's all about speed. Read the Research Article.

show that the PLD has the wide structural variation characteristic of other amyloid-forming proteins.
So to all intents and purposes, these and other observations confirm that Orb2 is a card-carrying amyloidogenic protein. But what allows it to function happily as an amyloid in the fly nervous system without causing a catastrophic neurodegenerative disease?
One possibility might be that the oligomers, increasingly fingered as the pathogenic agents, differ between "good" and "bad" amyloids. The authors had already noticed that Orb2 amyloids form surprisingly quickly and propagate with unusual stability as prions in yeast. To investigate this further, they directly compared the behavior of Orb2 and the Alzheimer amyloidogenic peptide Aβ42 in the test tube. Strikingly, Orb2 started to change conformation within minutes, while Aβ42 was stable for days (Fig 1).
What are the consequences of this for cells? The authors used chemical inhibitors to trap Orb2 in either the oligomeric form or the fibrous form and then injected them into cultured cells. As has been found for other amyloids, only the trapped oligomeric form of Orb2 (now made stable over time) caused widespread cell death.
Thus it seems that at least one of the differences between "good" and "bad" amyloids might lie simply in an aspect of their kinetics, namely the time dwelt in the oligomeric intermediate form.
To test this, the authors swapped the PLD of Orb2 with the polyglutamine tract from human mutant huntingtin protein-a well-studied pathogenic amyloid that causes Huntington "Good" and "bad" amyloids. Both pathological (red) and functional (green) amyloids can be inhibited at the beginning of the cascade by a common peptide (QBP1), and they both form toxic oligomers. However, the life span of the pathological species is much longer. Still, these two types of oligomers share enough similarities to form hybrid species, suggesting that the pathological amyloids may be sequestering the functional ones, thereby impairing their function. disease. Strikingly, huntingtin containing Orb2's PLD rapidly converted into a nontoxic amyloid, while Orb2 containing huntingtin's polyglutamine tract converted much more slowly via a highly toxic oligomeric state. Clearly, the kinetics and toxicity (fast and safe versus slow and deadly) are intrinsic properties of the respective amyloidogenic protein regions.
Given that "good" and "bad" amyloids behave so similarly in many respects, is there the possibility that they might influence each other when both are present? The authors tested this by coexpressing Orb2 and polyglutamine-containing huntingtin, finding that the toxic huntingtin coaggregates with Orb2. They speculate that toxic amyloids might have the ability to directly interfere with memory consolidation by mopping up functional amyloids of the CPEB/ Orb2 family.
The authors further showed that a peptide known to block the formation of pathogenic amyloids (QBP1) also blocks the formation of Orb2 amyloid (Fig 1), presumably because both types of amyloid are conformationally similar. But does this mean that while it can block the ill effects of "bad" amyloids, QBP1 can also interfere with the biological functions of "good" amyloids?
To address this, the authors engineered fruit flies so that they make QBP1-or a nonfunctional scrambled version-in all of their neurons. They then subjected the flies to a memory test in which males learn that it's not worth investing effort in courting unreceptive females. Neither QBP1 nor the scrambled version affected short-term memory, but when the males were tested 24 hours later, the males whose neurons contained QBP1 had forgotten the crushing disappointment of their previous amorous attempts, indicating a failure of long-term memory. The inference is that a peptide known to inhibit formation of "bad" amyloid can also inhibit important biological processes (such as memory consolidation) that depend on "good" amyloid, raising questions about the potential side effects of inhibiting amyloid formation in human patients.
Conversely, can blocking memory consolidation be beneficial? QBP1 or its chemical analogues may prove to be useful compounds to prevent the consolidation of traumatic or toxic memories in post-traumatic stress disorder and related diseases.
This study shows that the functional amyloid Orb2 shares a wide suite of properties with its pathogenic cousins, including conversion to a structurally characteristic insoluble fibrous deposit via a toxic oligomeric intermediate. However, a crucial difference seems to be the fleeting nature of Orb2's toxic form. Presumably evolution, while honing the functional amyloid for a biological purpose-the consolidation of memories-has selected for rapid kinetics that cut to the chase and minimize the chances of lasting damage. Pathogenic amyloids have not had that luxury.