Effect of Acetylation on Amyloid Beta Toxicity


Sometimes proteins misfold. When that happens in the human brain, the pileup of misfolded proteins can lead to neurodegenerative diseases like Alzheimer’s, Parkinson’s and ALS. In Alzheimer’s, these aggregates accumulate in the part of the brain that affects memory. It’s a disease that the Alzheimer’s Organization reports is the sixth leading cause of death in the US and will cost the nation about $250 billion in 2020. There is an urgent need  truly understand about the disease is that there is no single cause, no single trigger, and probably no silver bullet because of the chemistry involved. This is how a subtle change on a single position can affect a whole protein’s aggregation.

Proteins do not misbehave and misfold out of the blue. There is a delicate ecosystem of biochemical interactions and environments that usually let them twist, unfold, refold and do their jobs as they’re meant to. However, as researchers led by professor Ashutosh Tiwari from Michigan Technological University explore in an article published in ACS Chemical Neuroscience, even a small change may cause long-term consequences.

For  amyloid beta peptides which is considered a major hallmark of Alzheimer’s disease a common chemical modification at a particular location on the molecule has a butterfly effect that leads to protein misfolding, aggregation and cellular toxicity. To understand what causes the different shapes and to assess their toxicity, the authors looked at acetylation. Acetylation is one of the most common chemical modifications proteins undergo, but one of the least researched in terms of how it affects amyloid beta toxicity. On amyloid beta proteins, acetylation can occur at two sites: lysine 16 and lysine 28. The team found that acetylation at lysine 16 led to the disordered aggregates that formed sticky but flexible amorphous structures and showed high levels of toxicity. They also found the aggregates showed higher free radical formation. This is the first study wether acetylatation amyloid beta will change how the aggregate looks, then it changes its biophysical properties and hence toxicity. Indeed it is the shape, stickiness and flexibility of the aggregated protein structure which play a vital role in the cellular toxicity and may also affect the mechanism of toxicity.”

According to the authors, the effect of acetylation on tau, another protein aggregation, has been far more studied than amyloid beta. Also, many researchers still think a misfolded protein has to look a certain way to become problematic, and that other misfolded forms are less of an issue. The authors believed some of the proteins’ changes are subtle, and compares discerning the differences and their effects to snow tires. Snow tires have deeper treads and a more flexible material to handle winter roads, but it’s hard to point out those features at highway speeds. Like different kinds of tires, protein shapes can appear indistinguishable at a distance. When we do, we may better understand the complexity of the misfolded proteins and amyloid beta toxicity that can cause neurodegenerative diseases like Alzheimer’s.

Effect of Acetylation on Amyloid Beta Toxicity - Medicine Innovates
Cellular toxicity, which is higher in amyloid amorphous aggregates, shows that small changes in protein folding chemistry can cause differences in shape and toxicity. Credit: Ashutosh Tiwari
Effect of Acetylation on Amyloid Beta Toxicity - Medicine Innovates
Amorphous structures are made by misfolded proteins that form clumps; fibrils are misfolded proteins making long, stringy shapes. Credit: Ashutosh Tiwari


Dr. Ashutosh Tiwari is an associate professor at Michigan Technological University. He is a broadly trained protein chemist and cell biologist. His research is in the area of ‘protein aggregation diseases’ with special emphasis on age related neurodegenerative disorders such as Amyotrophic Lateral Sclerosis (ALS), Alzheimer’s disease (AD), Parkinson’s disease (PD), prion diseases, and Huntington’s disease (HD). In these diseases, misfolded proteins are observed as intracellular or extracellular aggregates at the end stage of the disease. However, the underlying mechanism(s) by which these aggregated proteins impair cellular function(s) and cause toxicity is not clear and is a subject of intense debate.

Tiwari laboratory is applying unique biochemical and biophysical approaches (including novel fluorescent molecules) to characterize the inherent vulnerability and instability of proteins associated with different neurodegenerative diseases. The long-term research goal of Tiwari lab is to understand consequences of protein misfolding and aggregation in vitro and how it relates to misfolding and aggregation in vivo, and its implication for neurodegenerative diseases.



Rashmi Adhikari, Mu Yang, Nabanita Saikia*, Colina Dutta, Wafa F.A. Alharbi, Zhiying Shan, Ravindra Pandey, and Ashutosh Tiwari. Acetylation of Aβ42 at Lysine 16 Disrupts Amyloid Formation. ACS Chem. Neurosci. 2020, 11, 8, 1178–1191

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