Amyotrophic lateral sclerosis (ALS) is a fatal neurological disease 
characterized by progressive motor neuron degeneration in association with 
neurofilament (NF) aggregate formation. This process is accompanied by an 
alteration in the stoichiometry of NF subunit protein expression such that the 
steady state levels of the low molecular weight NF (NFL) mRNA levels are 
selectively suppressed. We have previously shown that each of TDP-43, 14-3-3 and 
mutant SOD1 can function as NFL mRNA 3'UTR binding proteins that directly affect 
the stability of NFL transcripts. In this study, we demonstrate that the 
interaction of TDP-43 with the NFL mRNA 3' UTR involves ribonucleotide (UG) 
motifs present on stem loops of the 3'UTR as well as the RRM1 and RRM2 motifs of 
TDP-43. Ex vivo, TDP-43, 14-3-3 and SOD1 proteins interact to modulate NFL mRNA 
stability, although in vivo, only TDP-43 and either mutant or wild-type SOD1 
co-localize in ALS motor neurons. TDP-43 was observed to co-localize to RNA 
transport granules (Staufen immunoreactive) in both control and ALS spinal motor 
neurons. In contrast, both stress granules (TIA-1 immunoreactive) and processing 
bodies (P-bodies; XRN-1 immunoreactive) were more prevalent in ALS motor neurons 
than in controls and demonstrated strong co-localization with TDP-43. Using 
RNA-IP-PCR, we further demonstrate that NFL mRNA is preferentially sequestered 
to both stress granules and P-bodies in ALS. These data suggest that NFL mRNA 
processing is fundamentally altered in ALS spinal motor neurons to favour 
compartmentalization within both stress granules and P-bodies, and that TDP-43 
plays a fundamental role in this process.