Protein-linked Sugars Regulate the Spread of Alpha-synuclein, Study Suggests

Protein-linked Sugars Regulate the Spread of Alpha-synuclein, Study Suggests

A protein that has sugar molecules attached to it, called neurexin 1-beta, helps alpha-synuclein enter and accumulate within neurons contributing to the progression of Parkinson’s disease, a study has found.

The study, “Identification of N-linked glycans as specific mediators of neuronal uptake of acetylated α-Synuclein,” was published in PLOS Biology.

Parkinson’s is characterized by a build-up in the brain of the alpha-synuclein protein, which forms clumps known as Lewy bodies that damage and kill nerve cells, or neurons.

Cell-to-cell transmission of harmful alpha-synuclein protein appears to underly Parkinson’s propagation, and studies indicate there are components or properties of cellular membranes that are crucial for alpha-synuclein to get into cells.

“Indeed, specific components of the extracellular membrane, including proteins and proteoglycans [proteins with sugar molecules within them], have been identified as having roles in the uptake of pathogenic [alpha-synuclein] species,” the researchers wrote.

Changes in alpha-synuclein’s molecular structure — namely the addition of an acetyl group — have been found to alter its binding properties and rates of aggregation. But how these changes affect the protein’s binding to the cellular membrane remains unclear.

University of Pennsylvania researchers studied how these biochemical alterations changed alpha-synuclein “cellular behavior.” To do so, they used bacterial cultures, human-derived cellular cultures, and several biophysical methodologies.

Acetylated (with an added acetyl group) alpha-synuclein formed intracellular clusters in nerve cells more efficiently compared to an unchanged form of alpha-synuclein. No relevant studies have focused on acetylated alpha-synuclein molecular behavior, as this protein form is found in both normal and diseased neurons.

Removal of specific sugar molecules (glycans) found in the cellular membrane decreased the amount of alpha-synuclein that entered the cells. Of note, and among other things, the membrane surrounding cells is made of lipids (i.e., fat-like molecules) and proteins, predominantly those with added sugar.

Further biochemical analysis revealed that acetylated alpha-synuclein is structurally compatible to the same sugar molecules, and it is that proper molecular fitting that enables the protein to interact with the cell membrane.

Importantly, a neuronal glycoprotein — a protein with added sugar molecules — called neurexin 1-beta helped acetylated alpha-synuclein to get into cells.

Unchanged (not acetylated) alpha-synuclein’s behavior was not at all related to the sugar molecules, emphasizing the specific and important role of the latter in acetylated alpha-synuclein’s conduct.

“Some cells spontaneously internalize these [alpha-synuclein] proteins and some do not. It has generally been assumed that there are alpha-synuclein specific receptors on the cells that do internalize aggregates. That may or may not be true, but [our study] suggests that it’s not just the protein receptors but the glycans that are also important,” Elizabeth Rhoades, PhD, said in a press release. Rhodes is an associate professor of chemistry at the University of Pennsylvania, and the study’s lead author.

Having established that acetylated alpha-synuclein is a sugar-binding protein, scientists now have a new avenue to explore for the development of treatments for Parkinson’s disease.

3 comments

  1. Josekutty Joseph says:

    Does this mean the usage of ordinary sugar with food can worsen the progression of Parkinsons DIsease ?

  2. Philip Lindgren says:

    I’m not an expert by any stretch of the imagination. I was diagnosed with Parkinson’s about 2.5 years ago and have been studying various videos and papers from researchers, doctors and biologists on the internet looking at possible homeopathic, nutritional ways to slow down the progression of my ailment. I have also logged my symptoms and intake of certain foods, stress levels and exercise regiments over the same time period. I am convinced that a high carb and high sugar diet worsens my symptoms including a warm feeling down the back of my neck when eating large amounts of sugar (Ice cream, cake etc.). I have also noticed a bit more early morning body vibration and left hand twitching the morning after eating high carbs the night before. Additionally, I have also noticed a neck and shoulder warmth during high stress times. Exercise seems to counteract some of the symptoms. As a lay person, I am convinced the High Carbs and High Sugar is possibly the worst thing you can do to progress this (and other) degenerative brain disorders. I think this study is more proof and Sugar (Including carbs) is bad for your brain. Read Dr Perlmutter’s book “Grain Brain” good start

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