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Jul 10
2020

Research Bit: Epigenetic and transcriptomic studies of mutant C9orf72

Research Bits
The Packard Center welcomed Edward Lee, PHD from the University of Pennsylvania to a recent Investigator's meeting

Date: July 10, 2020

Presenter: Edward Lee, PhD

Talk Title: Epigenetic and transcriptomic studies of mutant C9orf72

What was the question being asked?

Work in Dr. Lee’s lab is broadly focused on understanding the pathogenic mechanisms underlying C9orf72 mediated neurodegeneration. A repeat expansion in the C9orf72 gene is the most common genetic cause of ALS and frontotemporal dementia (FTD). The Lee lab is specifically interested in evaluating how a loss of C9orf72 expression contributes to disease pathogenesis and relates to gain of function toxicity that can also result from the C9orf72 repeat expansion.

Why is this important for ALS research?

While most studies in the C9orf72 ALS/FTD field are focused on evaluating the biological consequences of pathologic repeat RNA and protein species generated by the C9orf72 mutation, there is conflicting evidence as to the contribution of loss of normal C9orf72 expression and function to disease. Additionally, the contribution of specific modifications to the C9orf72 gene itself and the global effects of this mutation on RNA expression are poorly understood. The work in Dr. Lee’s lab has begun to address these gaps in our knowledge.

What was the take-home message?

The Lee lab has generated critical reagents to evaluate the contribution of C9orf72 DNA modifications to disease pathogenesis and pathology. Additionally, they have early data that suggests RNA expression changes observed in C9orf72 are minimal in comparison to those in neurons lacking nuclear TDP (a pathological hallmark of the vast majority of ALS cases).  

How do you think the results of this study might impact future approaches to the treatment of ALS?

A thorough analysis of modifications to C9orf72 and their effects on disease pathology and biology is critical towards our understanding of C9orf72 ALS/FTD disease pathogenesis.

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