New evidence for shunned Parkinson’s theory
14 Jun 2012 by Evoluted New Media
A once-shunned theory on how Parkinson’s disease develops has received renewed support thanks to researchers in America.
Using powerful computational tools and laboratory tests, scientists from the University of California San Diego were able to provide a step-by-step explanation of how a ‘protein-run-amok’ aggregates within the membranes of neurons, puncturing holes in them to cause the symptoms of Parkinson’s.
This goes against the widely accepted theory that insoluble intracellular fibrils called amyloids cause the neurodegenerative disease.
Published in the FEBS Journal, the discovery describes how ?-synuclein (?-syn) monomers penetrate cell membranes, become coiled and aggregate in a matter of nanoseconds into dangerous ring structures.
Modelling revealed how two ?-syn proteins insert their molecular toes into the membrane of a neuron, wiggle into it and immediately join together. While the pair is not toxic, as more ?-syn proteins join, a key threshold is passed and polymerisation accelerates into a ring structure that perforates the membrane, damaging the cell.
“The most dangerous assault on neurons of Parkinson’s patients appears to be the relatively small ?-syn ring structures themselves,” said Igor Tsigelny, lead author.
“It was once heretical to suggest that these ring structures, rather than long fibrils found in neurons of people having Parkinson’s disease, were responsible for the symptoms of the disease; however, the ring theory is becoming more and more accepted for this neurodegenerative disease and others such as Alzheimer’s disease. Our results support this shift in thinking.”
The modelling is creating a better understanding of the ?-syn protein itself, and results are consistent with electron microscopy images of neurons in Parkinson’s patients. These discoveries have spawned an intense hunt for drug candidates that block ring formation in neuron membranes.
“We think we can create a drug that stops the ?-syn polymerisation at the point of non-propagating dimers,” Tsigelny said. “By interrupting the polymerisation at this crucial step, we may be able to slow the disease significantly.”
Role of ?-synuclein penetration into the membrane in the mechanisms of oligomer pore formation
