The Role of Ribonucleoprotein Aggregate Seeding in Alzheimer's Disease

Project Summary

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.