Figure 7: Proposed timeline for the progression of ROS-related molecular pathology in TDP-43-related proteinopathies.
From: Heat-shock protein dysregulation is associated with functional and pathological TDP-43 aggregation
The proposed model illustrates the sequential changes in the physical and chemical properties of TDP-43 polymers that occur in the presence of excess ROS and includes a novel 130-kDa TDP-43 oligomer that is involved in oxidative stress transduction. In healthy cells, the native monomeric TDP-43 C-terminus physically interacts with itself or with other prion-like domains to form functional aggregates. Elevated intracellular ROS levels typically occur during aging and in the early stages of neurodegeneration. In the presence of excess ROS, the HSP expression profiles are immediately altered in response to the repartitioning of TDP-43-associated HSPs, and TDP-43 is targeted to SGs and assembles into insoluble TDP-43 polymers. At later stages, the levels of toxic soluble 130-kDa TDP-43 oligomers significantly increases and affects redox signalling and cell viability. The ROS-induced sequential reassembly of TDP-43 polymers is the first indication of a TDP-43 proteinopathy. A second risk factor, such as inflammation, can cause further degradation of the TDP-43 C-terminus. The degraded TDP-43 C-terminal fragments form pathological inclusions. These TDP-43 inclusions induce ER stress following ROS generation, leading to massive neuron death and brain atrophy. Compounds that function at different stages in TDP-43 proteinopathies are indicated.
