Selection of DNA aptamers for inhibition of protein aggregation in ALS

A common feature in most ALS cases is a disruption of the normal levels and function of a protein called TDP-43. The protein is normally found in the nucleus of the cell, but in ALS, it accumulates in the cytoplasm and can form aggregates (clumps) that may be toxic. To target this TDP-43 pathology, Dr. DeRosa and team will explore the use of small molecules called DNA aptamers. These molecules can recognize and interact with specific biological targets with high precision. They function similarly to antibodies, but they are made of nucleotides (DNA) rather than proteins.

Dr. DeRosa hypothesizes that targeting a specific part of TDP-43 called the prion-like domain (PrLD) can preserve normal protein function and inhibit aggregation. By discovering unique sequences of DNA aptamers that can bind to the TDP-43 PrLD, they hope to inhibit accumulation of TDP-43 and reduce any associated toxicity.

TDP-43 dysfunction may be central to ALS pathology, making it a critical target for developing therapies to stop or slow disease progression. If successful, this project could bring a new therapeutic avenue for the field.

Collaborators: Dr. James Shorter

In 2006, the landmark discovery that 97% of ALS cases had abnormalities in the biology of a protein called TDP-43 shifted fundamental ALS research significantly. Soon after, it was determined that variants in the gene encoding TDP-43 could also cause ALS. The ALS Canada Research Program has supported more than thirty research projects investigating TDP-43 pathology in ALS, significantly impacting the field’s evolving understanding of this complex disease and leading us closer to effective treatments.