Provided herein are antigen-binding constructs such as antibodies that bind to the RRM-1 domain of TDP-43. The antigen-binding constructs are capable of blocking the interaction of TDP-43 with NF-κB in cells. Also provided herein are method of using the antigen-binding constructs in the treatment of diseases associated with TPD-43 proteinopathy, such as amyotrophic lateral sclerosis (ALS), frontotemperal lobar degeneration (FTLD), Lewy body disease and motor neuron disease.