The March issue of the FEBS Journal reports that scientists from the Californian University in San Diego have discovered new evidence for a theory that was once marginalized with regard to the underlying causes of Parkinson’s disease, which conflicts with an older theory that Parkinson’s and other neurodegenerative diseases are caused by insoluble intracellular fibrils called amyloids.
By using powerful computer tools and laboratory tests, the scientists managed to obtain a step-by-step explanation of how a “protein-run-amok” aggregates within the membranes of neurons, puncturing them and causing Parkinson’s disease symptoms. The process describes how α-synuclein (a-syn) can turn against us, especially as we get older. The results of the model demonstrate how α-syn monomers penetrate cell membranes and how they become coiled and aggregate within nanoseconds into dangerous ring structures that are harmful for neurons.
Lead researcher Igor Tsigelny, a research scientist at the San Diego Supercomputer Center and Department of Neurosciences at UC San Diego, declared:
“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.”
Numerous cases of familial Parkinson’s disease are caused by a limited number of protein mutations, the most toxic of which is A53T. Tsigelny’s team demonstrated that the mutant form of α-syn both penetrates neuronal membranes substantially faster compared with a normal α-syn, and that 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. 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 researchers discovered that their modeling results also proved consistent with electron microscopic images of neurons in Parkinson’s disease patients that have shown damaged neurons are riddled with ring structures.
The researchers immediately turned to search for drug candidates that can inhibit ring formation in neuron membranes. The highly complex modeling consists of various sophisticated scientific realms, which intersect between chemistry, physics, and statistical probabilities. A wide spectrum of interacting forces within this realm cause circumstances comparable to an earthquake, in which the a-syn proteins bump and tremble, coil and uncoil and join up in pairs or larger groups.
Even though researchers observed that the a-syn protein accumulated in the central nervous system of Parkinson’s patients and in those with a related disorder called dementia with Lewy bodies several years ago, Tsigelny says that the modeling creates a significantly better understanding of the a-syn protein itself.
The new modeling study precisely demonstrates how two α-syn proteins insert their molecular toes into a neuron’s membrane, penetrate into it within just a few nanoseconds and immediately join together as a pair that in itself is not toxic, however, as more a-syn proteins join, the key threshold is eventually overstepped, which results in an accelerated polymerization into a ring structure that perforates the membrane, which damages the cell.
According to Tsigelny, it may require many ring structures to actually kill neurons, which are generally very durable. Even though the nerve cells may be able to repair dozens of ring-induced perforations and are able to keep the pace with the a-syn assault up to a certain point, they will however at some stage be overtaken by the rate of perforations, which results in a gradual appearance of Parkinson’s symptoms that becomes worse.
“We think we can create a drug that stops the α-syn polymerization at the point of non-propagating dimmers. By interrupting the polymerization at this crucial step, we may be able to slow the disease significantly.”
The experimental validation studies were based on 3-D models of proteins, plus molecular dynamics simulations of the proteins, other modeling techniques and cell-culture experiments. Due to a deeper understanding of α-syn polymerization in neurons, the researchers now focus on gaining insight into how monomers of α-syn stick to one another. In their pursuit of finding drug candidates they will include molecules, which cause different a-syn protein conformations that are less inclined to stick together, as this effect, even if small, could decrease symptoms.
Pharmaceutical companies have used versions of this computationally intensive approach that includes examining many possible three-dimensional arrangements of α-syn dimers, trimmers and tetramers to develop drug candidates designed to bind to ‘anchor residues’ or ‘hot spots’ within target proteins. Virtual experiments of the theoretical ability of thousands of candidate drugs binding to human proteins in the ever-expanding database of known 3-D protein structures are assessed by algorithms. Even though promising candidates have been discovered using this approach, they regularly fail in clinical trials.
Tsigelny, a physicist who turned into a drug-designer explained:
“Out of these failures we’ve come to appreciate that proteins change their shapes so often that what would appear to be a primary drug target may be present one nanosecond, gone the next, or it wasn’t relevant in the first place.”
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. 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 neighboring molecules. We think it’s 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.”
Written By Petra Rattue