New Protein Modifiers and Therapeutic Targets to Combat Toxic RNA Foci in Frontotemporal Dementia

Bede Portz, PhD
Perelman School of Medicine at the University of Pennsylvania (Philadelphia, PA)


James Shorter, PhD
Year Awarded:
Grant Duration:
July 1, 2019 to June 30, 2021
Alzheimer's Disease
Award Amount:
Grant Reference ID:
Award Type:
Postdoctoral Fellowship
Award Region:
US Northeastern
Bede Portz, PhD

RNA Disaggregases as Regulators of RNA Phase-separation in C9orf72 Frontotemporal Dementia


Frontotemporal dementia is caused by expanded repeats in the C9orf72 gene, which encode toxic repeat RNAs that aggregate, forming RNA foci. I will elucidate the machinery overwhelmed by C9orf72 repeat expansion by testing the hypothesis that DDX3X is an RNA disaggregase capable of dissolving these foci, and by screening for new protein modifiers of C9orf72 RNA foci in live cells. This proposal will reveal basic RNA biology and identify novel therapeutic targets in frontotemporal dementia.


We seek to uncover new therapeutic targets in Frontotemporal Dementia (FTD). FTD typically strikes patients later in life and can be caused by toxic repeat RNA originating from genetic expansion of the C9orf72 (C9) gene. What proteins do neurons possess that allow them to stave off the harmful effects of C9 RNA until later in life, and why do they fail?

To answer these questions, we work at the intersection of biology and physics, where we study the aberrant phase-separation and aggregation of neurotoxic RNAs and the proteins they recruit. We endeavor to identify the proteins that prevent or reverse C9 RNA aggregation by employing both biochemistry and high-throughput screens. In our biochemical approach, we test candidates from a class of proteins known as RNA helicases for their ability to alter C9 RNA aggregates. These experiments represent a direct test of specific enzymes divorced from the complexity of the cellular environment. In contrast, our screening approach leverages recent advances in RNA-targeting CRISPR to search the genome for modifiers of C9 RNA aggregation in live cells in an unbiased way. This approach has the potential to uncover totally unexpected modifiers of C9 RNA toxicity that include those that act indirectly on C9 RNA aggregation. Hits from our genetic screen will be followed up with the direct biochemical assays under development in our first aim. Combined, our synthesis of biochemistry and unbiased screening is poised to uncover new genetic modifiers of C9 aggregation while also directly testing their effects in molecular detail.  We hope the proteins we uncover, and details of their inner workings we reveal, fuel the development of gene-therapy or small-molecule drugs to treat FTD.

About the Researcher

I am a postdoctoral researcher at the University of Pennsylvania Perelman School of Medicine, in the laboratory of Dr. James Shorter. I earned my Ph.D. in biochemistry from the Pennsylvania State University, where I worked in the highly collaborative and interdisciplinary Center for Eukaryotic Gene Regulation. There, I studied fundamental mechanisms regulating gene transcription and developed an interest in disordered proteins, as well as an emerging concept at the interface of biology and physics known as liquid-liquid phase separation. Phase-separation provides a theoretical framework for understanding how cells rapidly and reversibly organize specific components and processes in response to environmental changes. The aberrant phase-separation and aggregation of RNA-binding proteins and toxic repeat RNAs may represent the genesis of frontotemporal dementia and other neurodegenerative diseases. My desire to disentangle this relationship in molecular detail using experimental methods that span disciplines, motivated me to join the Shorter Laboratory. Here, with our collaborator, Dr. Ophir Shalem at the Children’s Hospital of Philadelphia, I combine biochemistry, cell biology, and high-throughput genetic screens, to identify new genetic modifiers of aberrant RNA and protein phase separation, and elucidate their mechanisms of action. It is my hope that both the data and experimental platforms my work will deliver will accelerate treatment of dementia. Following my postdoctoral training, I seek to launch my own laboratory, focused on understanding how cells use phase-separation as a means to compartmentalize specific processes, and how aberrant phase transitions contribute to disease.

Personal Story

I believe the most transformative science is happening at the intersection of traditional disciplines. My research goals reside at the interface of RNA and protein aggregation, RNA biology, biophysics, and biochemistry. I have been incredibly fortunate to train with scientific mentors who provided the freedom to explore questions across disciplines, and who encouraged me to nucleate new collaborations to empower that exploration.  The generous research support provided by the BrightFocus Foundation postdoctoral fellowship emboldens me to pursue new experimental strategies in a search for genetic contributors and potential therapeutic targets in frontotemporal dementia and other neurodegenerative diseases. I am grateful to my past and present scientific mentors, and the support of BrightFocus donors, whose contribution to my research will spur my transition to leading my own independent laboratory, where I will continue to investigate ways to counter FTD and other neurodegenerative diseases.

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