The ALS/FTLD-related RNA-binding proteins TDP-43 and FUS have common downstream RNA targets in cortical neurons

•We established TDP-43-silenced primary cortical neurons using lentivirus.•We compared TDP-43 and FUS transcriptome profiles in primary cortical neurons.•The sets of genes with altered expression levels upon TDP-43 knockdown or FUS knockdown overlapped by >25%.•The sets of genes with altered exon splicing upon TDP-43 knockdown or FUS knockdown overlapped by >9%.

TDP-43 and FUS are linked to amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD), and loss of function of either protein contributes to these neurodegenerative conditions. To elucidate the TDP-43- and FUS-regulated pathophysiological RNA metabolism cascades, we assessed the differential gene expression and alternative splicing profiles related to regulation by either TDP-43 or FUS in primary cortical neurons. These profiles overlapped by >25% with respect to gene expression and >9% with respect to alternative splicing. The shared downstream RNA targets of TDP-43 and FUS may form a common pathway in the neurodegenerative processes of ALS/FTLD.