Research Focus

A C9orf72 NRE DNA structure with a high-affinity compound docked in a novel pocket
Potential pathogenic mechanisms identified for C9orf72 NRE-linked disease
Focus I: Identifying NRE-Linked Disease Mechanisms
Focus II: Discovering novel therapeutic strategies for NRE-linked disease

In order to increase our understanding of NRE-linked diseases and to develop meaningful therapeutics, we must have robust NRE disease models. Therefore, our lab works on creating new NRE-linked disease models to understand pathogenic mechanisms of disease and to test any potential disease modulators. We are currently employing and creating  in silico, in vitro, and in vivo models to study NRE-linked diseases, with an emphasis on the C9orf72 NRE that is linked to neurodegenerative diseases such as ALS/FTD.

By understanding NRE-inked disease mechanisms, we can develop new therapeutic strategies to ameliorate NRE-linked pahtongenicity. We are taking a novel strategy to prevent NRE-linked disease by targeting the nucleic acids of the NRE directly. We believe this method will successfully target the root cause of disease and prevent the cascade of cellular events that eventually lead to neurodegeneration. Currently, we are examining small molecules as potential modulators of unique nucleic acid structures formed by the C9orf72 NRE.

NRE-linked disease mechanisms often include loss-of-function for the protein encoded by the mutated gene. However, there are two other toxic gain-of-function pathogenic mechanisms that have also been proposed: (1) the transcribed NRE region, can form RNA foci and sequester ribonucleoproteins, and (2) the repeat-containing RNA can undergo unconventional non-AUG-dependent translation, frequently referred to as repeat-associated non-AUG initiated (RAN) translation. Our lab is interested in investigating the contributions of loss- and/or gain-of-function mechanisms associated with NRE-linked, and to explore these pathogenic mechanisms we utilize the C9orf72 NRE-linked disease paradigm.

 
 
 
Focus III: Developing new models for
NRE-Linked Disease

Featured publications

 

Repeat-associated non-AUG translation in C9orf72-ALS/FTD is driven by neuronal excitation and stress. 2019, EMBO Molecular Medicine

Utilizing an ALS/FTD-linked C9orf72nucleotide repeat expansion (NRE) mutation model we provide new mechanistic understanding for the role of NRE-linked non-AUG translation in driving disease pathogenesis in neurons, such as increased stress and aberrant neuronal activity, and provide new therapeutic approaches to attenuate NRE-linked neurodegeneration.

Disclaimer
​The views expressed in this website may not reflect the views shared by the Jefferson Weinberg ALS Center, The Sidney Kimmel Medical College, the Vickie and Jack Farber Institute for Neuroscience, Jefferson and/or it's affiliates.