Taking a Look at Amytrophic Lateral Sclerosis (ALS)

Amyotrophic lateral sclerosis (ALS) presents as progressive weakening of all the voluntary muscles in the body due to the degradation of motor neurons. It is a severe motor neuron disease (MND) that is usually fatal within 5 years due to arrest of the respiratory muscles [Rowland, 2000]. It is only relatively recently that studies have defined specific gene mutations affecting protein function, giving some hope for finding an effective therapy for ALS. Currently there is no cure or treatment for the disease. Over the last five years discovery of mutations in two genes, transactive response (TAR) DNA-binding protein (TDP-43), so called because of its 43-kDa mass, and fused in sarcoma/transloacted in liposarcoma (FUS/TLS) have shifted research into trying to understand the roles of RNA metabolism in neurodegeneration. This micro-review will try to summarise what is known so far about TDP-43 and FUS/TLS and how they relate to pathogensis of ALS. TDP-43 was first identified in 2006 [Neumann, Sampathu and Kwong, et al., 2006] where it was shown there was a link between the protein and both ALS and frontotemperal lobar degeneration (FTLD). This study used double-labelling immunofluorescence to show that TDP-43 antibodies (antiTDP-43) immunolabelled ubiquitinated cytoplasmic, nuclear, and neuritic inclusions in sALS. However, it remained unclear how and what gene mutations were the underlying cause. This study observed that patients with ALS and FTLD had pathologic TDP-43. It