A Potential Approach to Reducing TDP-43 Proteopathy in the Aging Brain
Most neurodegenerative conditions are associated with the build up of damaging protein aggregates that degrade cell function or kill cells in the brain. The amyloid-β and tau of Alzheimer's disease and α-synuclein of Parkinson's disease are well known, but TDP-43 is not as well recognized beyond the that part of the research community focused on it. Here, scientists outline a potential approach to small molecule drugs that might reduce the tendency of TDP-43 to form aggregates. That is a first step on the road to therapies capable of slowing the progression of conditions such as amyotrophic lateral sclerosis (ALS) that are associated with TDP-43 pathology, but it is still a way removed from a full solution to the problem.
Researchers discovered that prolonged cellular stress, such as exposure to toxins, triggers TDP-43 clumping in the cytoplasm of human motor neurons grown in a laboratory dish. Even after the stress is relieved, TDP-43 clumping persists in ALS motor neurons, but not in healthy neurons. The team then screened and identified chemical compounds (potential precursors to therapeutic drugs) that prevent this stress-induced, persistent TDP-43 accumulation. These compounds also increased the survival time of neurons with TDP-43 proteins containing an ALS-associated mutation.
The researchers generated motor neurons from induced pluripotent stem cells (iPSCs) that had been converted from human skin cells. To mimic cellular aspects of ALS, they exposed these laboratory motor neurons to toxins such as puromycin, which stressed the cells and led to TDP-43 clumps. Normally, TDP-43 proteins help process molecules called messenger RNA, which serve as the genetic blueprints for making proteins. But when they clump outside the nucleus, TDP-43 proteins can't perform their normal duty, and that can have a profound effect on many cellular functions.
The researchers tested thousands of chemical compounds for their effects on RNA-protein aggregation. They were surprised to find compounds that not only reduced the overall amount of clumping by up to 75 percent, but also varied clump size and number per cell. Some of the compounds tested were molecules with extended planar aromatic moieties - arms that allow them to insert themselves in nucleic acids, such as DNA and RNA. TDP-43 must bind RNA in order to join ALS-associated clumps. Thus it makes sense that a compound that interacts with RNA would prevent TDP-43 from clumping.