PROJECT SUMMARY
This proposal uses innovative approaches to define an underlying molecular mechanism of the second most
common form of young onset dementia, frontal temporal dementia (FTD). There are no disease-modifying
treatment options available for FTD patients. A mutation in C9ORF72 (C9) is the most common cause of FTD.
This mutation leads to an abnormal excess of DNA structures, termed G-quadruplexes. Excess G-quadruplex
structures leads to the accumulation of toxic RNA and protein species and disrupts the transfer of materials
between the cytoplasm and nucleus. The net effect of these toxicities is neuronal degeneration and FTD onset.
Thus, C9 FTD is foundationally a ‘G-quadruplex disease’. Within the cell reside helicase enzymes that are
capable of unwinding G-quadruplexes. These enzymes have the potential to exacerbate C9 FTD by facilitating
the production of toxic RNA and protein species. This proposal seeks to determine the role of the major G-
quadruplex helicase, DHX36 (aliases: G4R1 and RHAU), in C9 FTD. DHX36 unwinds DNA and RNA G-
quadruplexes, modulates cellular stress response, and our preliminary data suggest a role for DHX36 in
nucleocytoplasmic transport. We hypothesize that reducing DHX36 levels will decrease the abundance of toxic
RNA and protein species and thus ameliorate C9 FTD disease. Similarly, we hypothesize that increasing DHX36
levels will increase the abundance of toxic RNA and protein and thus exacerbate the disease. We further
hypothesize that DHX36 modulates nuclear envelope structure and nucleocytoplasmic transport. We will test
these hypotheses using novel human neuronal cell lines and Dhx36-mutant-C9 FTD mouse models. Completion
of this work will potentially identify DHX36 as a novel therapeutic target affecting three of the major pathological
hallmarks of C9 FTD: toxic RNA foci, toxic dipeptide proteins, and aberrant nucleocytoplasmic transport. This
proposal builds on an existing collaboration between 4 research groups: Smaldino et al. (Ball State University),
Wang et al. (University of Virginia), Todd et al. (University of Michigan), and Vaughn et al. (Nanomedica. Inc.).
Each research group brings a complimentary set of expertise to pursue C9 FTD research. Undergraduate and
graduate students will be integrated at every stage in this project allowing them to gain authentic experience with
innovative technologies applied to a human disease, for which there is a striking absence of effective treatments.
This research presents a unique opportunity for students to make significant and impactful contributions to this
field.