Cellular mechanisms of ALS mutations – a loss or a gain of function?

TDP-43 and FUS are genetically and pathologically associated with amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD). I will summarize our recent advances in understanding the cellular mechanisms of disease causing mutations in FUS and TDP-43 and show evidence, which may suggest a loss of function component in ALS/FTLD. A loss of function appears to be the case for the FUS associated ALS causing mutations. Consistent evidence from several laboratories demonstrates that these mutations reduce nuclear transport by disturbing a PY-nuclear localization signal, which leads to a cytoplasmic accumulation of the mutant proteins. Additional stressors are then required to initiate aggregation probably via stress granules.