The new results conflict with an older theory that insoluble intracellular fibrils called amyloids cause Parkinson’s disease and other neurodegenerative diseases. Instead, the new findings provide a step-by-step explanation of how a “protein-run-amok” aggregates within the membranes of neurons and punctures holes in them to cause the symptoms of Parkinson’s disease.
The discovery describes how α-synuclein (a-syn), can turn against us, particularly as we age. Modelling results explain how α-syn monomers penetrate cell membranes, become coiled and aggregate in a matter of nanoseconds into dangerous ring structures that spell trouble for neurons.
“The main point is that we think we can create drugs to give us an anti-Parkinson’s effect by slowing the formation and growth of these ring structures,” said Igor Tsigelny of the San Diego Supercomputer Centre.
Familial Parkinson’s disease is caused in many cases by a limited number of protein mutations. One of the most toxic is A53T. Tsigelny’s team showed that the mutant form of α-syn not only penetrates neuronal membranes faster than normal α-syn, but the mutant protein also accelerates ring formation.
“The most dangerous assault on the neurons of Parkinson’s patients appears to be the relatively small α-syn ring structures themselves,” said Tsigelny. “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 results also are consistent with the electron microscopy images of neurons in Parkinson’s disease patients, the damaged neurons are riddled with ring structures.
Tsigelny’s approach takes advantage of classical drug-discovery algorithms, but adds additional analytical techniques to expand the search to include how a target protein’s conformations change in response to the forces operating on the scale of molecules.
“Sometimes, the drug-discovery models, despite being ‘nice looking,’ can be completely wrong,” Tsigelny said. “Scientists involved in drug discovery need to know when and to what extent to trust them. Even a slight shift in a cell’s environment can profoundly change the interactions of proteins with neighbouring molecules. We think it is realistically possible to design a drug to treat neurodegenerative diseases such as Parkinson’s disease and other diseases like diabetes with a more fundamental understanding of the proteins involved in those diseases.”
MEDICA.de; Source: University of California, San Diego