The Role of Ribonucleoprotein Aggregate Seeding in Alzheimer's Disease
Brain cells are made up of many different proteins that help them work correctly. Bad proteins can build up in the brain cells and cause them to become sick and die in Alzheimer’s disease. We want to study how a group of proteins known as ribonucleic acid (RNA) processing factors may cause bad proteins to build up in the cells. Results from the study may show us a new way to slow or stop the brain cell injury in Alzheimer’s disease (AD).
The abnormal accumulation of proteins both in and around neurons is a common feature in neurodegenerative disorders, including AD. These accumulations likely contribute to processes that lead to neuronal injury and ultimately the cognitive dysfunction that follows. We recently described a group of RNA processing factors that form abnormal protein aggregations in AD; however, it is unclear why they form and whether or not the RNA processing factor aggregations promote or seed the accumulation of other proteins, like tau. This proposal investigates the seeding capacity of RNA processing factors and specific protein domains that contribute to these abnormal protein accumulations. Findings from these studies could identify alternative approaches for developing novel AD therapies.
Our project studies how RNA processing factors promote or seed the abnormal accumulation of proteins in AD, thereby identifying novel approaches for targeting cellular mechanisms that lead to Alzheimer’s disease.
Recent studies suggest that tau seeding is important for the spread of abnormal protein accumulations in AD. Other proteins localize with tau-positive neurofibrillary tangles and may help drive this seeding process. We previously discovered candidates by studying AD-associated proteins from the brain, including RNA processing factors that accumulated with tau. These proteins formed cytoplasmic aggregations in the AD brain, and other data suggested that ribonucleoprotein aggregations may precede tau neurofibrillary tangle formation. At least one protein, U1-70k, also contained an aggregation-prone domain that may contribute to seeding. We therefore hypothesized that these RNA processing factors form intracellular protein aggregations that seed additional proteins.
First, this proposal investigates the seeding capability of RNA processing factors in a special cell culture model that senses whether these proteins promote abnormal tau accumulation. Similar parallel studies in rodent neurons and human induced pluripotent stem cell (iPSC) derived neurons will be performed to understand the specific effects on cells impacted in AD. Since elevated neuronal activity may contribute to abnormal protein seeding in the brain, the project also uses a model of neuronal hyper-excitability in rodent and iPS neurons on microelectrode arrays to identify seed-competent RNA processing factors secreted from these cells. Finally, we will study the in vivo seeding effects of RNA processing factors by injecting aggregation-prone domains into a mouse model of neurodegeneration.
The multifaceted approach investigates many important aspects of the seeding hypothesis, including the contribution of RNA processing factors; how cellular hyper-excitability drives the secretion of seed competent proteins; and in vivo RNA processing factor seeding in a mouse model of neurodegeneration. Many innovative approaches will be utilized, including in vitro seeding assays, human iPSC-derived neurons and multi-well microelectrode array electrical stimulation of both rodent and human neurons. Because we have incorporated human models into the experimental design, significant findings may more easily translated into viable therapies.
Overall, understanding how RNA processing factors contribute to the seeding of abnormal protein accumulations in AD is critical, because novel therapeutic targets are desperately needed. Although current amyloid and tau centric therapies may eventually show some efficacy, the best AD therapy may in fact be a multi-targeted approach, perhaps including mechanisms to disrupt the seeding and aggregation properties of RNA processing factors.
About the Researcher
Chad Hales MD, PhD, is an assistant professor in the Department of Neurology at Emory University School of Medicine in Atlanta, Georgia. He obtained a Bachelors of Science in biochemistry and molecular biology, with a minor in religion, from the University of Georgia (UGA) in Athens, Georgia. During his time at UGA, he gained an interest in research and completed his honors thesis investigating U3 small nucleolar RNA binding proteins under the guidance of Michael Terns PhD. He then matriculated at the Medical College of Georgia in Augusta, Georgia, for medical school and graduate studies, obtaining a PhD in molecular medicine under James Goldenring, MD, PhD, and Nevin Lambert PhD. Dr. Hales’ PhD studies focused on the small GTPase Rab11 and its role in intracellular trafficking and plasma membrane recycling. Following medical school, he moved to Emory for his medical internship, neurology residency including chief resident position, cognitive fellowship, and additional research training under Allan Levey MD, PhD, and Jim Lah MD, PhD at Emory, as well as with Steve Potter PhD in the Laboratory of Neuroengineering at Georgia Tech. Currently Dr. Hales’ research is focused on understanding the molecular mechanisms that contribute to AD, frontotemporal dementia and other neurodegenerative disorders. His laboratory utilizes a combination of basic cellular and biochemical techniques, including iPSC and derived lineages, as well as immunohistochemistry of postmortem human brain, proteomics, and cellular physiology with microelectrode arrays. He also continues to maintain an active role in teaching medical students and residents, as well as sees patients in the Cognitive Neurology Clinic, on the Emory University Hospital consult service, and by assisting with AD clinical trials.
I knew that I always wanted to be a physician; however, I learned through an undergraduate laboratory experience studying nucleic acids and proteins that I could do even more, by conducting research to understand the basic mechanisms of disease. Watching my grandfather succumb to the devastating effects of early onset Alzheimer’s disease (AD) was probably the first and greatest driving force behind my entire educational and professional path. Additionally and more recently, witnessing my mother-in-law struggle with a genetic form of frontotemporal dementia has continued to provide additional fuel.
The clinical training throughout residency, fellowship and beyond has provided me with such an amazing view of how various neurological disorders, including AD and other neurodegenerative disorders manifest clinically. The training and personal life experiences also continuously highlighted the struggles that caretakers live with on a daily basis. At the same time, further research training introduced me to the power of neuropathological observation, proteomic sequencing, human cell models, cellular physiology and other biochemical/cellular techniques as approaches to gain insight into disease pathogenesis.
I am most grateful to the BrightFocus Foundation and donors for providing me with this opportunity to investigate how RNA processing factors contribute to the AD neurodegenerative process. Of course, the ultimate goal is to use the skill set I have been developing, along with my clinical research trial experience, to translate basic findings from this and other laboratory studies into therapies for our patients and families.
First published on: July 10, 2017
Last modified on: April 20, 2020