More than 10 million people worldwide have Parkinson’s disease, which is progressively debilitating and, at present, incurable. Now, Texas A&M AgriLife researchers have found a new way to study the disorder’s progression on a molecular level. The team has also obtained new clues toward a treatment.
For continued work on the project, the National Institutes of General Medical Sciences has given the Outstanding Investigator Award and $1.4 million in funding to Dmitry Kurouski, Ph.D., assistant professor in the Texas A&M College of Agriculture and Life Sciences Department of Biochemistry and Biophysics.
Parkinson’s disease causes leaks in some neurons
In patients with Parkinson’s, a normally benign protein called alpha-synuclein starts to behave abnormally — but only in some neurons. A healthy neuron contains many identical copies of alpha-synuclein. In Parkinson’s patients, these copies tend to form big clusters, or aggregates. Neurons containing such aggregates become “leaky” and eventually die. With time, more and more neurons are affected. Yet in other neurons in the same brain, alpha-synuclein does not aggregate to the same extent and does not cause problems.
Alpha-synuclein may behave in such different ways in different neurons because of what else is in the cells. For example, alpha-synuclein interacts with lipids, a class of molecules that are the chief components of cell membranes. Related to this, several research groups have shown that alpha-synuclein can disrupt cell membranes and make them leaky.
Learning more about how different lipids and alpha-synuclein interact may answer why alpha-synuclein is toxic in some neurons but not others. However, studying this phenomenon has been challenging. Alpha-synuclein can aggregate into vastly different shapes, like water forming into snowflakes, snowballs, icicles or icebergs. The aggregates’ varied and shifting shapes confound several techniques that researchers might use to study them.
A method Kurouski recently developed turns out to be quite useful for studying the interaction of alpha-synuclein and lipids. Kurouski and his team are using two sophisticated techniques they previously used on variously shaped virus particles — nano-Raman spectroscopy and nano-infrared spectroscopy.
Indeed, for the Parkinson’s project, the techniques are already providing information about the folds, lipids and amino acids on alpha-synuclein aggregates’ surface and in their core.
“What we have discovered is that the structure and toxicity of alpha-synuclein can be uniquely altered by lipids,” Kurouski said. This work recently appeared in the Journal of Physical Chemistry Letters.
Next, the team will investigate further how cell membrane components such as cholesterol affect alpha-synuclein toxicity. The researchers plan to study these effects in cultured cells and in cells from Parkinson’s patients.
Overall, the team aims to determine why alpha-synuclein has toxic effects only in some neurons. The researchers hypothesize that the toxicity of alpha-synuclein aggregates is determined by their structure. That structure, in turn, is controlled by the lipid composition of neuronal membranes.
“With age and other factors, the brain’s lipid composition changes,” Kurouski said. “If we find that a certain lipid composition promotes alpha-synuclein toxicity, could we then find a treatment or a diet to mitigate it?”
Tianyi Dou, a graduate student in Kurouski’s lab, has been conducting the spectroscopy experiments.
“Even though what we are doing may not cure the disease directly, it is essential to understand the mechanism of why the aggregates become toxic,” Dou said. “It is a hard project, and we are trying our best to explore the missing pieces.”
A project years in the making
Kurouski first studied diseases related to protein aggregates as a graduate student. He always wanted to come back to that topic in his own laboratory, he said.
“When I started the lab, we started working on Parkinson’s, and it took several years to build instrumentation for the structural analysis that now we can do,” Kurouski said. “We tested the method first in viruses and saw that it can work exceptionally well for characterization of small biological objects.”
Eventually, a look at diseases other than Parkinson’s
The team plans to use the same method to study protein aggregates linked to Alzheimer’s, Huntington’s and prion diseases.
“These different problems may show synergy or open more questions,” Kurouski said. “We want to understand whether what we are describing is a general phenomenon.”