More than 10 million people worldwide have Parkinson’s disease, which is increasingly debilitating and currently incurable. Today, researchers at Texas A&M AgriLife have found a new way to study disease progression at the molecular level. The team also got new clues to a cure.
For further work on the project, the National Institutes of General Medical Sciences awarded the Outstanding Investigator Award and $ 1.4 million in funding to Dmitry Kurouski, Assistant Professor at Texas University A&M College of Agriculture and Life Sciences Department of Biochemistry and Biophysics.
In patients with Parkinson’s disease, a normally benign protein called alpha-synuclein begins to behave abnormally, but only in certain neurons. A healthy neuron contains many identical copies of alpha-synuclein. In patients with Parkinson’s disease, these copies tend to form large clumps or aggregates. Neurons containing such aggregates become “leaky” and eventually die. Over time, more and more neurons are affected. However, in other neurons in the same brain, alpha-synuclein does not aggregate to the same extent and does not cause problems.
Alpha-synuclein can behave so differently 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 main components of cell membranes. In this context, several research groups have shown that alpha-synuclein can disrupt cell membranes and make them permeable.
Learning more about how different lipids and alpha-synuclein interact may explain why alpha-synuclein is toxic in some neurons but not in others. However, the study of this phenomenon has been difficult. Alpha-synuclein can aggregate in very different forms, such as water turning into snowflakes, snowballs, icicles, or icebergs. The varied and changing shapes of aggregates confuse several techniques that researchers could use to study them.
A method recently developed by Kurouski is proving very useful for studying the interaction of alpha-synuclein and lipids. Kurouski and his team use two sophisticated techniques they previously used on viral particles of various shapes: nano-Raman spectroscopy and nano-infrared spectroscopy.
Indeed, for the Parkinson project, the techniques already provide information on the folds, lipids and amino acids on the surface of alpha-synuclein aggregates and in their nucleus.
“What we found is that the structure and toxicity of alpha-synuclein can be uniquely altered by lipids,” Kurouski said. This work was recently published in the Journal of Physical Chemistry Letters.
Next, the team will study in more detail 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 patients with Parkinson’s disease.
Overall, the team aims to determine why alpha-synuclein only has toxic effects in certain neurons. The researchers hypothesize that the toxicity of alpha-synuclein aggregates is determined by their structure. This structure, in turn, is controlled by the lipid composition of neuronal membranes.
“With age and other factors, the lipid composition of the brain changes,” Kurouski said. “If we find that a certain lipid composition promotes alpha-synuclein toxicity, then could we find a treatment or regimen to alleviate it?”
Tianyi Dou, a graduate student from Kurouski’s lab, conducted the spectroscopy experiments.
“Even though what we are doing does not directly cure the disease, it is essential to understand the mechanism that explains why the aggregates become toxic,” said Dou. “It’s a tough project, and we’re doing our best to explore the missing pieces.”
Kurouski first studied diseases related to protein aggregates as a graduate student. He always wanted to come back to this topic in his own lab, he said.
“When I started the lab, we started working on Parkinson’s disease, and it took several years to build the instrumentation for the structural analysis that we can now do,” Kurouski said. “We first tested the method on viruses and found that it could work exceptionally well for the characterization of small biological objects.”
The team plans to use the same method to study protein aggregates linked to Alzheimer’s, Huntington’s and prion diseases.
“These different issues can show synergy or open up more questions,” Kurouski said. “We want to understand if what we are describing is a general phenomenon.”