The human TAR DNA-binding protein-43 (TDP-43) and C09ORF72 genes have been recently identified as being mutated in patients with amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). Despite great interest, the normal and pathological function of TDP-43 and C09ORF72 is poorly understood. Exploiting the specific strengths of the C.elegans model, we aim to define the normal function of TDP-43 and C09ORF72. The C.elegans genome contains single orthologs for TDP-43 (
tdp-1) and C09ORF72 (F18A1.6). We have called F18A1.6 "
alfa-1" for ALS/FTD Associated gene homolog. Deletion alleles for
tdp-1(
ok803,
ok781) and
alfa-1(
ok3062) were made available to us through the C.elegans knockout consortium. Animals lacking
tdp-1 or
alfa-1 are viable, fertile, and appear superficially normal. We have back-crossed the
tdp-1 and
alfa-1 mutants four times to wild-type worms (N2 strain) and performed behavioral analysis of motor function. We observed an age-dependent decline in locomotory activity of
tdp-1 and
alfa-1 mutants, as assessed by thrashing and crawling velocity assays. These locomotory defects are unlikely to be caused by synaptic transmission defects, as
tdp-1 and
alfa-1 mutants did not display any aldicarb sensitivity defects. In addition, we have begun to determine the expression pattern and subcellular localization of
tdp-1 and
alfa-1 by generating isoform-specific fosmid-based translational reporters for TDP-1 (isoforms a-c) and ALFA-1 (isoforms a-b). We have observed that the long
tdp-1 isoforms (TDP-1a and TDP-1c) display a rather broad, nuclear expression pattern, including head neurons, muscle cells, and intestine. In contrast,
alfa-1 expression appears cytoplasmic and restricted to pharyngeal cells and non-neuronal tail cells. We are currently analyzing in further detail the expression pattern of
tdp-1 and
alfa-1 isoforms to design tissue-specific rescue experiments for the locomotory defects. Defining the normal function of
tdp-1 and
alfa-1 in a simple animal model may hold the key for understanding how mutations in these loci cause neurological defects in humans.