2014-2015 Alzheimer’s and Related Diseases Research Award*

Investigating the Role of miR-762 in Mediating Disease in C9ORF72-Based Frontotemporal Degeneration

VCoA*The Virginia Center on Aging which administers the Alzheimer’s and Related Diseases Research Award Fund for the Commonwealth of Virginia, provides seed money to researchers in Virginia to stimulate innovative research into biomedical and psychosocial aspects of dementia, including cell biology, caregiving, and animal modeling.

Investigating the Role of miR-762 in Mediating Disease in C9ORF72-Based Frontotemporal Degeneration

Erin Pennock Foff, MD, PhD and Benjamin Purow, MD

University of Virginia

Frontotemporal Degeneration (FTD) is a common cause of neurodegenerative dementia, particularly in the early-onset population (prior to age 65). This ultimately fatal disease is biologically linked to Amyotrophic Lateral Sclerosis (Lou Gehrig’s disease), and the familial forms and some sporadic cases have been shown to share underlying genetic defects. The most common known cause of such familial cases is the expansion of the 6-nucleotide repeat in the gene, C90RF72, whose normal biologic function remains unknown. The investigators have identified a regulatory molecule, known as microRNA-762 (miR-762), that is predicted to bind tightly to the expanded repeat. They have pilot data to support their hypothesis that this effectively “sponges” the miR, rendering it unable to perform its normal biologic function, but crucial experiments are needed to define the role that this mechanism may play in causing disease. This study will use human cell lines obtained from C90RF72-positive patients to demonstrate the sponging effect in vitro, and compare the cellular expression profile to patients with the disease, but without the repeat expansion. Future experiments will investigate whether a common and safe anti-seizure medication can alter available miR-762 levels in an attempt to develop a disease-modifying therapy in FTD patients.


It is known that amyotrophic lateral sclerosis and frontotemporal dementia can be caused by a common genetic mutation in the C9ORF72 gene. The investigators discovered that a particular regulatory microRNA had high predicted affinity to bind this mutation, and questioned whether inappropriate binding of that molecule could contribute to disease process. In this funded project, they were able to demonstrate that: a) the predicted microRNA shows altered activity in blood and stem cells derived from patients with the disease, b) specific genes are misregulated in the cells in a manner consistent with microRNA disruption, and c) those disruptions may be contributing to some of the known features of the disease, including excitotoxicity to glutamate. These results constitute the most critical first steps in validating the investigators’ proposed mechanism’s potential role in mediating part of the disease phenotype.  This initial data has also contributed to a new initiative in the lab to build more sophisticated model systems using three-dimensional stem cell cultures that will better approximate normal brain structure and cellular interactions.

(Dr.Foff may be contacted at 434/243-1006, epf4b@virginia.edu; Dr. Purow may be contacted at 434/982-4415, bwp5g@virginia.edu)



More 2014-2015 Funded Projects