Biochemistry of Protein Misfolding
Disaggregases and Protein Misfolding: A Q&A
Meredith Jackrel, Ph.D.
Assistant Professor of Chemistry
at Washington University School of Medicine in St. Louis
Meredith Jackrel, Ph.D., an Assistant Professor of Chemistry at Washington University in St. Louis, researches the biochemistry of protein misfolding with a focus on the role of disaggregases. The Longer Life Foundation is a proud supporter of Dr. Jackrel’s research into restoring proteostasis to counter human disease.
Q:
How did you first become interested in scientific research, and in your area of interest?
A:
I have long had an interest in science. When I was an undergraduate at the College of New Jersey, I became interested inunderstanding how science progresses, and how people can better understand basic life processes. From there I got involvedwith laboratory research and became increasingly interested in biochemistry.
Q:
Your current research focuses on the misfolding of proteins and the numerous disorders and disease processes it influences. Indeed, protein misfolding underpins many devastating neurodegenerative disorders, including Alzheimer’s disease, Parkinson’s disease, Huntington’s disease, and amyotrophic lateral sclerosis (ALS). How much is known about what actually causes proteins to misfold in the first place? Might it be due to a common pathway or could the cause be unique to each disease?
A:
We still do not really understand what specifically initiates protein misfolding. In some cases, genetic mutations are present that increase the likelihood of a specific protein to misfold. This is particularly true fordisorders such as Huntington’s disease. However, in most of these disorders, it remains unclear what triggers misfolding to initially occur. There are certain common pathways implicated in multiple disorders, but there are also unique aspects to each disorder.
There are certain common pathways implicated in multiple disorders, but there are also unique aspects to each disorder.
Q:
You are particularly interested in disaggregases, which aid in the solubilizing (dissolving) of misfolded proteins, as well as in the employment of protein engineering techniques to fine-tune the properties and capabilities of these disaggregases. How did you come upon this path of research and at what point are you now?
A:
When I was a postdoctoral fellow at the University of Pennsylvania, I was in a group thatwas studying Hsp104, a protein found in baker’s yeast which can eliminate misfolded proteins.
Yeasts are unusual in that they can use different types of protein conformations to rapidlyadapt to changing conditions. The proteins that yeast regulate in this process are strikingly similar in shape to those that aggregate in human disease. We became very interested in understanding how the yeast proteins do this. At the time, it was thought that humans did not possess these disaggregases, but we now know that humans do have different types of disaggregases. One hypothesis is that disaggregases preserve proteins in their proper shape but are prone to failure with age. We are continuing to research the utility of Hsp104 as a possible therapeutic or even as a probe to help us better understand how we might counter these disorders. We also are interested in studying and improving the activity of various human disaggregases.
Q:
For what conditions besides neurodegenerative diseases might your research be applicable?
A:
Protein misfolding is implicated in numerous disorders. We recently published work on proteins that aggregate in sarcoma, a type of cancer. We are also interested in applying our work to protein misfolding that can drive cardiovascular disease and antimicrobial resistance.
Q:
Is there any evidence to suggest that reversing or removing misfolded proteins could improve or resolve clinical symptoms once manifested or is it too early to say?
A:
At this point it is a bit too soon to say if reversing misfolding might improve or resolveclinical symptoms, but recent results have been very promising. There is also some evidence that certain forms of these misfolded proteins may be toxic, while others may be protective, so it could be somewhat complicated to determine precisely which species (protein types) must be eliminated.
Q:
I understand you are in the earlier stages of research, but do you believe disaggregases might someday be used both preventatively and therapeutically?
A:
We are eager to explore this idea. It is a bit too soon to say if disaggregases will find clinical use, but we are very optimistic that they may ultimately be used therapeutically.
To read about Dr. Jackrel’s newest work on developing vaccine technologies for seniors, please click here
Meet the Investigators
Blood Cancer
Grant Challen, Ph.D
Predicting – and Preventing – Blood Cancer? An Essential Conversation.
A recent recipient of funding from The Longer Life Foundation, Dr. Grant Challen, Associate Professor Department of Medicine, Oncology Division and Stem Cell Biology at Washington University…
Metabolism, Nutrition, and Aging
Bettina Mittendorfer, Ph.D.
Metabolism, Nutrition, and Longevity: Finding the Keys
Biochemistry of Protein Misfolding
Meredith Jackrel, Ph.D.,
Disaggregases and Protein Misfolding: A Q&A
Convalescent Plasma (CP)
Convalescent Plasma and COVID-19
Human Aging
Calorie Restriction and the Future of Aging
Polycythemia Vera
