TDP-43 and ALS - what's wrong with my membranes?

In recent years, multiple pathologies of the mRNA binding protein TDP-43 have been linked to the neurodegenerative disease Amyotrophic Lateral Sclerosis (ALS), in which almost 97% of all ALS patients exhibit TDP-43 abnormalities in affected neurons. Typically, neuronal degeneration first affects alpha motor neurons of the spinal cord and the lower brainstem, before the disease progresses to Betz cells, giant neurons of the primary motor cortex, and subsequently spreads into further brain regions. It is just the Betz cells though, which do not show cytosolic TDP-43 aggregation upon loss of nuclear TDP-43 expression, but instead display membrane defects in organelles such as the Golgi apparatus, the ER and the nuclear envelope. In this review, we will therefore examine connections between TDP-43 and inner membrane systems, with a particular focus on nuclear and the ER membranes. In doing so, we will summarize evidence suggesting that the disease may have an early onset, potentially even prenatally, and describe how interactions between TDP-43 and the lipid metabolism as well as connections with membrane components, may drive cells towards ALS as time goes by.