Almost 90% of ALS is thought to be sporadic. The reasons are not well understood and thought to be oxidative stress, damaged endoplasmic reticulum, mitochondria, cytoskeleton or misregulation of RNA pathways. One protein implicated is TDP43 which sits as a junction of ALS pathogenic path by binding to RNA modulation synthesis, splicing, stability and transport. Its is essential for survival of cells and by forming aggregates of TDP43 may lead to absence from the nucleus. Its over expression causes similar neurodegenerative phenotypes as the mutants. These mutants can cause increased half life and stability and hence implicating TDP-43 as one of the key measures in proteinopathies.
TDP43 is self regulated and since it is part of a multi-protein RNA complex, any changes in TDP43 may cause a corresponding change in the activity of the complex. The aggregate hypothesis assumes that increasing TDP43 causes aggregation thus leading to a complex state where more TDP43 becomes catalytic and drives aggregation in a positive aggregation loop.
Experiments have shown that knocking out TDP43 or misregulating its expression in motor neurons of mice also induces motor neuron degeneration phenotype which may implicate its role as a dominant-negative mechanism. The role of TDP43 in other non motor neuron cells, such as astrocytes, may be equally important and there may be a connection to the spread of TDP43 proteinopathy.
