Endogenous alpha-synuclein protein levels (green) in a coronal brain section of a Lewy bodies-injected monkey. Image credit: Vall d'Hebron Institut de Recerca VHIR(CC BY-ND 2.0)
Alpha-synuclein is a protein that is essential for brain function. Like all proteins, alpha-synuclein is made of a string of amino acids and folded up in a precise way. Misfolding of this protein can lead to a buildup of protein clumps in the brain. These clumps cause neurodegenerative diseases like Parkinson’s disease, Parkinson’s disease with dementia, dementia with Lewy bodies, and multiple system atrophy.
Each of these diseases affects different parts of the brain and has distinct symptoms. Studying the misfolding patterns and structures of proteins collected from the brains of deceased people who had these conditions may help scientists understand the differences. Scientists also try to recreate these misfolded proteins in the laboratory using a seeding amplification assay technique. This is important as scientists can only extract limited amounts of protein clumps from human brains. However, it is unclear if the laboratory-produced protein clumps behave exactly like brain-derived clumps. Learning more is essential to make sure that studies of these proteins produce accurate results.
Lee et al. identified differences between alpha-synuclein clumps extracted from patients with different brain diseases. They also show that laboratory-derived protein clumps do not exactly recreate those from patients. Clumps from patients with Parkinson’s disease, Parkinson’s disease with dementia, dementia with Lewy bodies, and multiple system atrophy have straight and twisted protein structures when examined under an electron microscope. But the laboratory-generated clumps for Parkinson’s disease, Parkinson’s disease with dementia, and dementia with Lewy bodies are all straight. Laboratory-generated clumps for multiple system atrophy are all twisted. The clumps from patient brains also have many phosphate groups attached to them. Laboratory-derived clumps of Parkinson’s disease with dementia and dementia with Lewy bodies also had this feature. However, the lab-derived versions of the other disease clumps lack this characteristic.
Lee et al. identify essential differences between the protein clumps from the brains of patients with different neurodegenerative diseases. They also found that the laboratory-generated clumps do not completely replicate all their features. More research is needed on these disease-specific differences and how they contribute to specific disease symptoms and disease progress. Work is also required to refine laboratory processes for protein clumps to replicate disease-associated clumps better. More studies could help scientists develop better laboratory models for these diseases that can be used to create and test new therapies.
