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Aug 9
2019

Research Bit: Oligonucleotides to disrupt aberrant phase transitions in ALS

Research Bits
The Packard Center welcomed Chris Donnelly from the University of Pittsburgh to a recent Investigator's Meeting.

Meeting Date: 9 August 2019

Presenter: Chris Donnelly

Talk Title: Oligonucleotides to disrupt aberrant phase transitions in ALS

What was the question being asked?

TDP-43 is considered a pathological hallmark of ALS. While normally located predominantly in the cell nucleus, in the majority of ALS cases, this protein becomes pathologically mislocalized to the cytoplasm and often times forms cytoplasmic aggregates thus inhibiting its normal function. TDP-43 is also known to localize to stress granules in multiple ALS model systems. Stress granules are membrane-less liquid like structures that are normally protective and form during times of cellular stress to aid in recovery. It is thought that this pathological cytoplasmic accumulation is the result of aberrant and prolonged stress granule formation. However, there is little existing evidence to support this hypothesis. The studies conducted by the Donnelly lab aim to identify whether liquid like properties of TDP-43 underly its accumulation into pathological cytoplasmic aggregates. 

Why is this important for ALS research?

Mutations in TDP-43 are causative of a small percentage of ALS cases. However, TDP-43 pathology is present in over 97% of all ALS cases. Thus, understanding how TDP-43 pathology occurs is crucial to our understanding of ALS pathogenesis and may provide insight into useful therapeutic strategies that may prove beneficial for the majority of ALS patients. 

What was the take-home message?

Using both cell culture and fly model systems, the Donnelly lab uses light to induce liquid phase transitions and subsequent aggregation of TDP-43. While individual pulses of light result in reversible TDP-43 oligomeric interactions, sequential pulses of light over time leads to a decrease in the ability of TDP-43 to recover from these liquid light states and thus, TDP-43 takes on a more solid, aggregate-like form. Intriguingly, this phenomenon occurs when TDP-43 is unable to bind to RNA and custom designed oligonucleotide sequences specifically targeted to TDP-43 can prevent TDP-43 aggregation in a dose dependent manner. A similar phenomenon is observed with the ALS associated protein FUS where additional experiments demonstrated that addition of RNA to pre-formed FUS fibrils can actually disassemble FUS aggregates. Together, these results suggest that RNA binding to TDP-43 and FUS is protective against its pathological aggregation.  

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

These studies open up a potential new avenue for therapeutics, namely the use of designer oligonucleotides for decreasing accumulation of aggregation prone proteins such as TDP-43 and FUS. In the future, it is possible that this approach may also prove beneficial for aggregation prone proteins in other neurodegenerative diseases. 

Alyssa Coyne, Ph.D.
Postdoctoral Fellow, Rothstein Lab
Johns Hopkins University School of Medicine
Department of Neurology

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