Note: Single-source report; awaiting corroboration.
Several neurodegenerative diseases—including amyotrophic lateral sclerosis (ALS), frontotemporal dementia (FTD), and some Alzheimer’s cases—are linked to abnormal clumping of the TDP-43 protein outside the nucleus of brain and nerve cells. This aggregation leads to neuron death and symptoms such as muscle weakness and memory loss. TDP-43 normally functions in the nucleus to regulate RNA processing essential for proper cell activity.
Past studies indicated that certain RNAs interacting with TDP-43 might inhibit or reverse its aggregation, suggesting a potential therapeutic approach. Short RNAs are appealing as treatments due to their ease of delivery to neurons. However, the mechanism by which short RNAs prevent TDP-43 clumping was previously unclear.
An NIH-funded research team led by Dr. James Shorter at the University of Pennsylvania investigated this and reported their findings in Science. They confirmed that a specific short RNA, Clip34, stabilizes RNA-binding regions of TDP-43, reducing its tendency to aggregate. Clip34 was effective in vitro in preventing aggregation of both normal and mutated TDP-43 proteins. Researchers also optimized Clip34’s sequence to prevent aggregation of additional abnormal TDP-43 forms.
The team identified several other short RNAs, with the most effective named Malat1_start, which could reverse aggregation of isolated TDP-43 protein even after aggregates had formed. Malat1_start also reduced induced TDP-43 clumping inside cells without disrupting the protein’s normal functions. Both Malat1_start and Clip34 restored TDP-43’s proper nuclear location in motor neurons derived from ALS patients. Moreover, Malat1_start improved TDP-43’s functions that were impaired in stressed motor neurons.
In animal models, Malat1_start partially reversed TDP-43 aggregation in motor neurons, offering further insight into RNA-based interventions for diseases associated with abnormal TDP-43 aggregation.