Amyotrophic lateral sclerosis (ALS) is characterized by the nuclear depletion and cytoplasmic aggregation of an essential RNA/DNA binding protein, TDP-43. TDP-43 is a key constituent of neuronal ribonucleoprotein (RNP) granules involved in post-transcriptional mRNA regulation, including splicing, mRNA localization and translation of transcripts important for synaptic and axonal maintenance. We and others have previously shown that ALS-linked TDP-43 mutations in the LCD impair axonal transport of RNP granules. Specifically, we found that mutations in the conserved helical segment and flanking residues have the most severe effects on TDP-43 transport. However, the molecular mechanisms underlying TDP-43 mutant transport defects are unclear. Recent evidence suggests RNP granules positive for TDP-43 and other RNA-binding proteins hitchhike on lysosomes and/or other organelles. Hence, the objective of the present study is to determine whether mutations in the aforesaid domains disrupt the co-trafficking of TDP-43 RNP granules with lysosomes or endosomes. We performed live cell microscopy of rodent primary cortical neurons expressing eGFP-tagged wild type or mutant forms of TDP-43, endosomal marker and lysotracker. Our observations showed that approximately half of wild type TDP-43 granules co-traffic with lysosomes while the remaining ones travel independent of lysosomes. In line with our previous findings, TDP-43 mutations overall reduce long range RNP granule motility, but lysosomal transport is preserved. The few mutant RNP granules that do show movement are moving independently of lysosomes. In ongoing work, we are also studying the lysosome-independent transport mechanism using the split kinesin assay and analyzing the co-transport with endosomal markers.