Scientists at the University of Bath have discovered a series of protein structures that are thought to be highly relevant to the onset of Parkinson’s disease (PD).
Their findings, “A series of helical α-synuclein fibril polymorphs are populated in the presence of lipid vesicles,” is published in Nature Partner Journal-Parkinson’s Disease and led by Jody Mason, PhD, professor in the department of biology & biochemistry at the University of Bath.
Parkinson’s disease is a progressive nervous system disorder that affects movement. Symptoms start gradually, sometimes starting with a barely noticeable tremor in just one hand. As the disease progresses, people may have difficulty walking and talking. More than 10 million people worldwide are affected by PD and it is the second most common neurodegenerative disease after Alzheimer’s disease. Parkinson’s disease is caused by a loss of nerve cells in the part of the brain called the substantia nigra. Nerve cells in this part of the brain are responsible for producing a chemical called dopamine.
Alpha-synuclein (αS) is currently an important focus among PD researchers. It is a protein that is abundant in the human brain, and is also present in other body tissues such as the heart, muscle, and gut. αS is normally a wavy-like structure but in Parkinson’s, the αS protein misfolds forming a toxic clump or aggregate. During this process, the early aggregations are very reactive and believed to cause damage to cellular components. They also go on to accumulate in large masses termed “Lewy bodies” which are clumps of specific substances within brain cells are microscopic markers of PD.
The researchers examined how αS misfolds in the presence of phospholipids. They observed a series of misfolded protein structures that have never been seen before. These αS fibers were larger than any previously reported. The fibers ranged in a variety of shapes including flat ribbons, and long, wave-like helices.
“To date, a significant proportion of structural information has arisen from in vitro studies using recombinantly purified forms of the protein, often failing to acknowledge that αS is natively located in the presence of phospholipids, where it likely plays a direct role in regulating synaptic vesicle function and neurotransmission. Here we present a series of macromolecular αS assemblies not previously described that form in the presence of lipid vesicles. These fibrillar structures are striking in both their large size relative to those previously reported and by their varying helical content, from ribbons to wave-like helices of long pitch shortening to those more compact and bulkier,” the researchers wrote.
The researchers were able to observe the structures using transmission electron microscopy “… Lipid-induced fibril production has been shown to be strongly affected by early-onset mutations, which can induce dramatic changes in such crucial processes thought to be associated with the initiation and spreading of αS aggregation. Phospholipid biosynthetic enzymes have also been seen to be elevated in the substantia nigra of PD patients. Specific membrane interactions can therefore play a key role in triggering a conversion of αS from a soluble to aggregated form that is associated with disease,” the researchers noted.
“We know that these misfolded proteins are heavily implicated in Parkinson’s disease,” said Mason. “What’s more, alpha-synuclein is known to be important given its interaction with brain cell membranes. Further analysis of these structures will open up a door of understanding and may one day lead to a potential treatment for Parkinson’s disease.
“By advancing our understanding of the different structures of the protein that are likely to be present inside brain cells, this University of Bath study helps pave the way for developing treatments that may one day stop the progression of Parkinson’s,” Mason added.
