Yifat Miller’s chemistry lab at Ben-Gurion University reveals the atomic structure of a fragment of a brain protein that triggers Parkinson’s.
By Avigayil Kadesh Is there a link between Type 2 diabetes (T2D) and neurodegenerative diseases such as Parkinson’s disease (PD)? Yes, says Dr. Yifat Miller, whose chemistry lab at Ben-Gurion University in Beersheva is the first in the world to reveal the atomic structure of a fragment of a brain protein, alpha-synuclein, known to trigger PD by aggregating (clumping) and causing the death of neurons.
Miller’s team does its studies using sophisticated computer simulations, and tests the hypotheses with partner bio-chem labs. “To study the link between T2D and PD, we first had to overcome the problem of finding the atomic structure of alpha-synuclein,” she says. “Publishing these results will allow other scientists to use this information to learn more about Parkinson’s, its mechanisms and possible drugs to reduce aggregation,” says Miller, who set up her Israeli lab in 2011 after three years of post-doctoral research on Alzheimer’s disease at the National Institutes of Health in Maryland. Her lab’s previous studies indicate that people with T2D face twice the risk of developing Alzheimer’s disease (AD) later in life compared to those who do not have diabetes. A peptide that causes T2D is in pancreas and brain Insulin is not the only critical substance involved in diabetes, she explains. “Many people know that T2D is related to a problem with lack or loss of insulin, but many don’t know there is another protein that is also related, called Amylin. Amylin is a peptide or a short chain of amino acids that is found in the pancreas of 95 percent of T2D patients. We’re still learning its mechanisms and effects,” says Miller. “What is interesting about Amylin is that it is an endocrine hormone located not only in the pancreas but also in the brain. We hypothesize that in the brain it could have an effect on neurodegenerative diseases.” When Amylin aggregates in the pancreas, it harms insulin-producing beta cells and therefore causes T2D. Amylin can clump in the brain as well, with the help of a peptide called amyloid beta already proven to be involved in the development of AD. “It was known that this aggregation causes the death of neurons, but no one knows how these two protein molecules aggregate at the atomic resolution,” Miller says. “Last year at the American Biophysical Society, we did a presentation on the interactions between beta amyloid and Amylin at the atomic resolution that can also happen in the brain. Recently, we claimed that other proteins in the brain can also interact with Amylin. One brain protein related to Parkinson’s is alpha-synuclein. “To learn more about Parkinson’s in our lab, we needed to know the atomic structure of this protein — and its aggregates in particular — because they are neurotoxic.” Her lab focused only on the snippet of alpha-synuclein – non-amyloid-beta component (NAC) — previously identified as the culprit in harmful aggregation activity in PD. They are the first to publish the atomic structure of NAC aggregates. Amazing synergy “Now that we know the atomic structure of NAC aggregates, we want to look at the interactions between NAC and Amylin aggregates and how these interactions are related to the link between T2D and PD. When we looked at their interactions as aggregates, we found an incredible synergy. It’s amazing how each one of these peptides induces aggregates in the other,” says Miller. “This is an important finding, because now one could develop a drug to prevent these interactions to lower patients with T2D be at high risk for developing Parkinson’s.” Miller says it has been known since around 1990 that people with T2D also have a higher risk for PD, especially when the diabetes strikes at younger ages. “However, the link between the two diseases is still unknown, and no one knew so far the atomic resolution of how NAC and amylin aggregate together and kill neuron cells. This is really important and novel, with broad interest.” Yifat, a mother of four daughters, reveals that her studies have a personal connection. “My grandfather passed away from T2D and he developed Parkinson’s toward the end,” she says. Her team — four graduate students and one post-doctoral researcher — works on many projects related to neurodegenerative diseases. This project of almost three years was led by PhD candidate Yoav Atsmon-Raz. This research is funded by the European Union Seventh Framework Programme. “Our lab may continue investigating this further because there is a lot to do,” she says. “Our work provides a lot of information for new studies to understand the mechanism of PD. Perhaps the problem of regulating insulin contributes to PD. We have some ideas of developing a drug to prevent the interactions between NAC and Amylin aggregates.”