Family experience guides Alzheimer’s research

After watching his father struggle with and ultimately succumb to Alzheimer’s disease, ASU professor Michael Sierks shifted his research focus from starch hydrolyzing to neurodegenerative diseases.

“It’s a terrible disease, so I started thinking if there was anything I could do,” recalls Sierks, who is an associate professor of chemical and materials engineering in the Ira A. Fulton School of Engineering.

Sierks’ expertise is in protein engineering. He uses a cutting-edge toolkit to manipulate proteins vital to our health. When Sierks read about the role of the protein beta-amyloid in Alzheimer’s, he jumped at the chance of entering a new field. He began working on Alzheimer’s and other closely related diseases, such as Parkinson’s and Huntington’s disease.

“We’ve been making some really encouraging progress,” Sierks says. “We’re isolating antibodies that can alter the aggregation properties of alpha-synuclein, which is the protein involved in Parkinson’s.”

Sierks uses custom-made antibodies to prevent the proteins from tangling. Acting similar to a Teflon-coated cooking pan, the designed antibodies, which recognize and attach to the faulty protein, keep the proteins from sticking together.

His groundbreaking research on specific forms, or morphologies, of antibodies for treating Parkinson’s has caught the attention of many health organizations and sponsors.

Sierks and his team from ASU soon will begin working on a three-year project funded by the Arizona Disease Control Research Commission (ADCRC) to further his research on developing antibody-based therapeutics primarily for Parkinson’s disease.

The grant essentially is a continuation from a prior two-year study funded by the ADCRC. Sierks also has received $250,000 in funding for this project from the Michael J. Fox Foundation.

Parkinson’s disease is the second-most prevalent neurodegenerative disease, following Alzheimer’s disease. According to the National Parkinson’s Foundation, it is estimated that 1.5 million Americans are afflicted with Parkinson’s.

Parkinson’s results in disturbances in motor function and is characterized by tremors, rigidity and bradykinesia (slowness of movement).

The protein alpha-synuclein has been strongly correlated with Parkinson’s. Its use is similar to the techniques used in origami, as the protein can take on many shapes and sizes, both folded and unfolded.

Although it is a natively unfolded protein, it can adopt a number of different folded conformations. If a protein doesn’t fold correctly, it doesn’t perform its function, which can be toxic itself or lead to other harmful effects.

Sierks’ team at ASU has been collaborating with doctors at the New York State Department of Health’s Wadsworth Center in Albany for the last two years to develop a tool to control the formation of different alpha-synuclein morphologies.

His team will be responsible for isolating antibodies that recognize different aggregate forms of alpha-synuclein.

“The idea is to find what we really want to target as a therapeutic for Parkinson’s disease,” Sierks says. “The antibodies that promote the health of the cells are not only going to tell us what the right target is, they’re also going to be potential therapeutic antibodies by themselves.”

The antibodies that decrease toxicity potentially represent a therapy for treating Parkinson’s, and the antibodies that stabilize the toxic forms of alpha-synuclein can be combined with a second antibody activity to target and clear the toxic forms from neurons. This catalystic antibody strategy has proven to be effective for targeting and killing tumor cells.

If these techniques prove to be successful, they can be used to study other diseases caused by protein aggregation.

Sierks’ prior work on alpha-synuclein aggregation was published in the March 16 issue of Biochemistry 2004.