Amyotrophic lateral sclerosis (ALS) is an incurable neurodegenerative disease 
that preferentially targets motor neurons. It was recently found that dominant 
mutations in two related RNA-binding proteins, TDP-43 (43-kDa TAR DNA-binding 
domain protein) and FUS/TLS (fused in sarcoma/translated in liposarcoma) cause a 
subset of ALS. The convergent ALS phenotypes associated with TDP-43 and FUS/TLS 
mutations are suggestive of a functional relationship; however, whether or not 
TDP-43 and FUS/TLS operate in common biochemical pathways is not known. Here we 
show that TDP-43 and FUS/TLS directly interact to form a complex at endogenous 
expression levels in mammalian cells. Binding was mediated by an unstructured 
TDP-43 C-terminal domain and occurred within the context of a 300-400-kDa 
complex that also contained C-terminal cleavage products of TDP-43 linked to 
neuropathology. TDP-43 C-terminal fragments were excluded from large molecular 
mass TDP-43 ribonucleoprotein complexes but retained FUS/TLS binding activity. 
The functional significance of TDP-43-FUS/TLS complexes was established by 
showing that RNAi silencing of either TDP-43 or FUS/TLS reduced the expression 
of histone deacetylase (HDAC) 6 mRNA. TDP-43 and FUS/TLS associated with HDAC6 
mRNA in intact cells and in vitro, and competition experiments suggested that 
the proteins occupy overlapping binding sites. The combined findings demonstrate 
that TDP-43 and FUS/TLS form a functional complex in intact cells and suggest 
that convergent ALS phenotypes associated with TDP-43 and FUS/TLS mutations may 
reflect their participation in common biochemical processes.