The Alzheimer’s Mystery: Why Proteins Clump Up and Kill Our Memories

Matthias Truttmann, PhD
University of Michigan (Ann Arbor, MI)
Year Awarded:
2019
Grant Duration:
July 1, 2019 to June 30, 2020
Disease:
Alzheimer's Disease
Award Amount:
$100,000
Grant Reference ID:
A2019157S
Award Type:
Standard
Award Region:
US Midwestern
Matthias Truttmann

The Impact and Mechanistic Basis of Chaperone AMPylation in the Development and Progression of Alzheimer’s Disease

Summary

Proteins are small particles that enable us to think and store memories. As we get older, these proteins become less and less stable and will occasionally engage in the formation of protein clumps within cells. Some of these protein clumps are very toxic to neurons and will damage our brains, thus triggering neurodegenerative diseases such as Alzheimer’s disease. We aim to better understand the processes that prevent the formation of such protein clumps and seek to learn why these processes become less efficient in the older population.

Details

Our work examines the impact and mechanistic basis of chaperone regulation in the development and progression of Alzheimer's disease. Chaperones are small molecular machines required for the repair and disposal of damaged proteins. Dysregulation of chaperone activity facilitates the formation of protein clumps characteristic for Alzheimer's disease. Recently, it was discovered that chaperones are regulated by a chemical modification called AMPylation. The goal of our research project is to define how chaperone AMPylation levels correlate with Alzheimer's disease onset and development. We will examine human brain samples from Alzheimer's disease patients as well as controls using high-content microscopic imaging and biochemical approaches to elucidate how chaperone AMPylation might contribute to this disease. Our approach combines exciting novel techniques and experiments that allow us to define the chaperone AMPylation status in both fixed or frozen human brain tissue. The results from our work will dramatically increase our understanding of how chaperone AMPylation regulates protein aggregation and represent the first in-depth analysis of protein AMPylation levels in human brains. Since the regulation of chaperone activity is critical in all aggregation-associated neurodegenerative diseases, including Parkinson's disease, Huntington's diseases or inherited spinocerebellar ataxias, our work will have implications beyond Alzheimer's disease. Our ultimate long-term goal is to explore and exploit the pharmacological modulation of chaperone AMPylation as a novel avenue to combat Alzheimer's disease.

About the Researcher

I received my undergraduate training in molecular biology at the Biozentrum, University of Basel, Switzerland. For my Masters training in biochemistry and biophysics, I joined a Basel-based biotech company and worked on the inhibition kinetics of TEM-type b-lactamases. I then joined the laboratory of Dr. Christoph Dehio at the Biozentrum, University of Basel, Switzerland to pursue my doctoral studies. As a graduate student in infection biology, I worked on elucidating how pathogenic bacteria hijack host cell signaling in order to enable their own internalization. Following my graduate training, I spend almost two years working as a financial consultant for a major consulting company in Switzerland before I was willing to admit that scientific research gave me the most satisfaction. I thus quit my job and joined the lab of Dr. Hidde Ploegh at Whitehead Institute for Biomedical Research / MIT in Boston as a postdoctoral fellow. As a postdoc, I started to work on a novel post-translational protein modification called AMPylation. I generated nematode-based models to examine the impact of protein AMPylation on organismal physiology, co-solved the structure of a metazoan AMPylase and discovered direct links between chaperone AMPylation and protein aggregation dynamics. Since July 2018, I am a Principal Investigator and Assistant Professor in the Department of Molecular and Integrative Physiology as well as a Research Assistant Professor in Gerontology at the Medical School, University of Michigan. With my laboratory, I examine how post-translational protein modifications, such as AMPylation, regulate protein aggregation in neurodegenerative diseases and aging.

Personal Story

Curiosity has always been my companion. As a student, I had the reputation of being a notorious asker of why? and how?, a habit that continuously tested the patience of my parents, teachers and mentors. As a teenager, I would often day-dream of discovering something meaningful, maybe a forgotten ancient culture or a cure for a major disease. It was always clear to me that I would eventually pursue a profession in which the search for answers was the overarching goal. After watch the movie Outbreak starring the likes of Dustin Hofman, Rene Russo and Morgan Freeman, I became interested in how small changes in a cell’s protein composition can cause complex disease phenotypes. I thus decided to get training in biomedical research. In the past 10+ years, my work has focused on cellular stress signaling and how pathogens or misfolded proteins trigger and overwhelm it. My training has been a fascinating journey and I'm very grateful for it to continue, which wouldn't be possible without the generous support of BrightFocus and its donors. Now, as a principle investigator leading my own laboratory, I intend to foster my student’s curiosity and offer them a rewarding environment that maximally fuels their creativity. It might be their work that one day changes the faith of many patients for a better life.

Publications

Porter, C.M., Truman, A.W. and Truttmann, M.C., 2020. Post-translational modifications of Hsp70 family proteins: Expanding the chaperone code. Journal of Biological Chemistry, pp.jbc-REV120. PMID: 32518165 PubMed Icon Google Scholar Icon

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