Proteins — large molecules made up of amino acids — do most of the work in cells and are required for the structure, function, and regulation of the body’s tissues and organs. A confluence of circumstances leads the proteins to twist, unfold, and refold the way they are meant to for regular functioning — but sometimes that process breaks down and the proteins misfold.
The human brain contains a delicate ecosystem of biochemical interactions and environments. In the brain, misfolded proteins can accumulate into aggregates, which can lead to neurodegenerative diseases such as Amyotrophic Lateral Sclerosis (ALS), Parkinson’s disease, and Alzheimer’s disease.
Researchers from Michigan Tech found that even a small change in the brain’s ecosystem can cause long-term consequences. In an article titled “Acetylation of Aβ42 at Lysine 16 Disrupts Amyloid Formation” published in ACS Chemical Neuroscience, the Michigan Tech scientists explore these small changes and how they relate to dementias such as Alzheimer’s disease.
Acetylation of Amyloid Beta Proteins
Amyloid beta proteins are considered to be an indicator of Alzheimer’s disease. A common chemical modification at a specific location on this molecule has a butterfly effect — it can cause the protein to misfold, subsequent aggregation of misfolded proteins and cellular toxicity. According to Ashutosh Tiwari, a professor in Michigan Tech’s Department of Chemistry, misfolded amyloid beta proteins aggregates can then form stringy fibrils or balled-up amorphous structures. In order to understand what causes the different protein aggregate fibrils and balled-up structures and to assess whether they cause cellular toxicity, the team of scientists examined acetylation.
Acetylation is one of the most common modifications that proteins undergo, but it is also one of the least researched in terms of how it affects amyloid beta toxicity. For amyloid beta proteins, acetylation can occur at lysine 16 and lysine 28. Acetylation at lysine 16 leads to the disordered aggregates that form sticky, flexible amorphous structures and show high levels of toxicity. This is due to the fact that lysine 16 acetylated amyloid beta peptide forms amorphous aggregates instead of amyloid fibrils. “The shape, stickiness, and flexibility of the aggregated protein structure can play a vital role in the cellular toxicity and may also affect the mechanism of toxicity,” said Tiwari.
What Does This Mean for Alzheimer’s Disease?
In Alzheimer’s disease, aggregates accumulate in the part of the brain that affects memory. Understanding this complicated chemistry is key to understanding the causes of the disease as there is no single cause or trigger.
Many researchers think that a misfolded protein has to look a certain way to be problematic. But according to Tiwari, “A subtle change on a single position can affect a whole protein’s aggregation.” Discerning the differences between these subtle changes can be like distinguishing between the shallow treads of regular tires and the deep treads of snow tires while driving at highway speed. Snow tires have deeper treads and a more flexible material in order to handle snowy conditions, but that is tough to feel while navigating a snowy road at 60 mph. Similarly, protein shapes and misfolds — some harmless, some detrimental — can appear indistinguishable at a distance.
Looking at protein structures more closely and deeply from morphological and biophysical perspectives is important. This will enable researchers to better understand the complexity of the misfolded proteins and the amyloid beta toxicity that can contribute to neurodegenerative diseases. This understanding of the diseases’ contributing mechanisms could in turn lead to new preventative measures or treatment options.
Worldwide, 50 million people are living with Alzheimer’s disease and other dementias. June is Alzheimer’s and Brain Awareness Month, and QPS joins the Alzheimer’s Association in raising awareness and inspiring action.
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