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...
Source: Fight Aging! - Category: Research Authors: Tags: Daily News Source Type: blogs