A New Approach to Understand Why Defects in the Lysosome Pathway Increase the Risk of Developing Alzheimer's Disease

Thomas Kukar, PhD
Emory University (Atlanta, GA)
Year Awarded:
Grant Duration:
July 1, 2019 to June 30, 2022
Alzheimer's Disease
Award Amount:
Grant Reference ID:
Award Type:
Award Region:
US Southeastern

Understanding Lysosome Dysfunction in Alzheimer's Disease


The health and survival of neurons in the brain is dependent on a recycling pathway carried out by lysosomes, cellular organelles that help degrade and recycle proteins. Defects in the function of lysosomes are increasingly thought to be involved in the development of Alzheimer’s disease (AD). We are trying to understand why decreases in a protein called progranulin impair lysosome function and increase the risk of developing Alzheimer's disease. This research will help our long-term effort to develop drugs to treat Alzheimer's disease by correcting lysosome function.


Increasing evidence suggest that dysfunction of lysosomes, a critical component within cells, plays a key role in the development of Alzheimer’s disease (AD). The health and survival of neurons in the brain is dependent on lysosomes, cellular organelles that help degrade and recycle proteins. We are trying to understand why decreases in a protein called progranulin impair lysosome function and increase the risk of developing AD. This research project will help our long-term effort to develop drugs to treat AD by correcting or boosting lysosome function to prevent neurodegeneration.

This research proposal focuses on the role of endosome-lysosome dysfunction in AD and related dementias, such as frontotemporal dementia (FTD). Mutations or SNPs in the GRN gene, which encodes the progranulin (PGRN) protein, increase the risk of developing AD or FTD by decreasing the levels of PGRN.  We have discovered that PGRN is trafficked to the lysosome and processed into stable granulin proteins (called GRNs), which we hypothesize play a key role in lysosome health and function. However, the function of GRNs is unknown. In this project, we will identify the binding partners of PGRN and GRNs in the endosomal-lysosomal network to gain insight into their function. We will also generate a transgenic (tg) TMEM192 mouse, that can be used to isolate lysosomes and will have broad utility in the AD and neurodegenerative field, because they will allow investigators to evaluate lysosome dysfunction and rescue in vivo. Further, they can immediately be used in the many AD mouse models that have already been generated to provide a deeper understanding of AD pathogenesis. Moreover, tgTMEM192 mice can be used for in vivo in and cell type or mouse model thus will have broad application to many fields beyond AD.

About the Researcher

Dr. Thomas Kukar received his B.S. in Microbiology & Cell Science and a Ph.D. in Medicinal Chemistry, both from the University of Florida. His post-doctoral fellowship was at the Mayo Clinic in the Laboratory of Todd Golde, M.D., Ph.D. in the Department of Neuroscience, where he studied the role of the Amyloid Precursor Protein (APP) and the amyloid-beta (Aβ) peptide in AD pathogenesis. He played a key role in the development of gamma-secretase modulators (GSMs) as potential drugs for AD. Following his post-doc, he was promoted to an Associate Consultant and Assistant Professor of Molecular Neuroscience in the College of Medicine at Mayo Clinic. Dr. Kukar left Mayo Clinic and started his independent research laboratory in 2010 at Emory University in the Department of Pharmacology in the School of Medicine and was promoted to Associate Professor in 2018. He has received a number of awards including the Alzheimer’s and Parkinson’s Disease Conference Junior Faculty Award, the National Institutes of Health’s Pathway to Independence Award (K99/R00), and the Charleston Conference on Alzheimer’s Disease (CCAD), Outstanding Early Career Investigator in Alzheimer’s Disease Award. Dr. Kukar’s research goals are to understand the causes of age-associated neurodegenerative diseases with a long-term goal to develop treatments. His laboratory studies Alzheimer’s disease (AD), frontotemporal dementia (FTD), and amyotrophic lateral sclerosis (ALS). The research in Dr. Kukar’s lab has been funded by the BrightFocus foundation, the Alzheimer’s Association, the Association for Frontotemporal Degeneration, The Bluefield Project to Cure Frontotemporal Dementia, and the NIH. In his limited free time, he likes to play guitar, cycle around Atlanta, go see live music, and go hiking and camping.

Personal Story

Growing up I was always fascinated by the natural world, with science, and the brain in particular. Seeing my grandfather struggle with and eventually succumb to Alzheimer’s Disease was devastating but had a profound impact on my life’s direction and career path. When I went to college I enrolled in the pre-med curriculum at the University of Florida, because I thought becoming a neurologist would be the best opportunity to have the greatest impact on people afflicted with AD. However, as I shadowed doctors and learned more about AD, it was clear how little we truly knew about the disease. It was also apparent that there were no treatments to stop or even slow the inevitable cognitive decline of AD. After doing research as an undergraduate in a lab, I got bit by the research bug and I realized scientific research was my calling and an incredible opportunity to make a difference. So I changed course and applied to graduate school where I decided to dedicate my career to investigating the mysteries of the brain with the aim to uncover the causes of AD and related neurodegenerative diseases. I hope this project helps my laboratory’s goal to understand the mechanisms of AD and ultimately develop a cure. Our lab and many others around the lab have made huge strides in understanding AD and I’m optimistic about the future. I’m extremely grateful to the donors at BrightFocus for their generosity and the opportunity to help further our mission to end this terrible disease.

Don't miss out.
Receive research updates, inspiring stories, and expert advice
Please enter your first name.
Please enter your last name.
Keep me informed about: *
Please select at least one.
You must select at least one disease category.