Loading...
Loading...
2 mins read
A new study suggests that polyphosphate, an essential biological polymer, could be the key behind a mysterious density in fibrils associated with Alzheimer's and Parkinson's diseases. This molecule, which appears to stabilize the fibrils and reduce their toxicity, opens the door to new strategies for slowing the progression of these devastating diseases. The understanding of fibrils has improved thanks to new tools and methods, among which cryo-electron microscopy (cryo-EM) stands out, an advanced technique that allows observing the fibrils in great detail.
For a long time, scientists have established that fibrils, which are small filaments formed by amyloid proteins, are linked to various neurodegenerative diseases. Their presence has been documented in the brains of patients, but important questions remain about how they accumulate in the body and their influence on the progression of these disorders.
In 2020, an international team of researchers from Cambridge used cryo-EM to uncover a mysterious mass within the fibrils extracted from patients with a neurodegenerative disease known as multiple system atrophy. Although they managed to characterize the fibrils down to the level of the individual amino acids that make up the protein structure, an unknown material persisted along the fibrils, which they called 'mysterious density' (Schweighauser et al., 2020).
Recently, research led by the University of Michigan has provided evidence that could clarify the composition of this unknown material in fibrils associated with Alzheimer's, Parkinson's, and other neurodegenerative diseases. This study suggests that a common biological polymer called polyphosphate could be the cause of this mysterious density. Polyphosphate is a molecule present in all living beings and has been present throughout evolution. It is also considered to be related to various neurodegenerative diseases.
The study demonstrated that polyphosphate helps stabilize the fibrils and reduces their potential harm to cultured neurons. Other research has shown that the amount of polyphosphate in the brains of rats decreases with age. These findings suggest that polyphosphate could be essential in protecting humans from neurodegenerative diseases. However, direct evidence of its relevance in the human body is still lacking. The human brain is a highly complex environment, and so far, no experiment has been developed to clarify the role of polyphosphate in it. However, thanks to previous research, scientists have precise 3D structures of human fibrils. Using computational models of these structures, they conducted simulations to observe how polyphosphate would interact with a fibril and found that it perfectly matched the mysterious density. Subsequently, they modified the fibril structure by changing the amino acids surrounding the mysterious density. Testing these variants, they observed that polyphosphate was no longer associated with the fibrils and did not protect neurons from their toxicity.
Since it is not possible to extract polyphosphate from fibrils derived from patients, it cannot be confirmed that it is indeed the mysterious density. However, there is solid evidence suggesting that the mysterious density corresponds to polyphosphate. This study hypothesizes that maintaining adequate levels of polyphosphate in the brain could slow the progression of neurodegenerative diseases. However, proving this will require significant investments of time and resources, and new enigmas are likely to arise along the way. We are still at a very early stage; only recently has it become evident that there are additional components in these fibrils. These components may play a crucial role, or they may have no role at all. But only if all the puzzle pieces are in place can we hope to successfully combat these devastating diseases.
Sources