To identify the best target epitopes in vivo, we screened peptide antigens covering all regions of TDP-43 for active immunization, and investigated their effects on TDP-43 phosphorylated at serines 409/410 (pTDP-43), transcriptional alterations, neuroinflammation, and neuroaxonal damage in an aggressive mouse model of TDP-43 proteinopathy. The gene discussed is TARDBP; the disease is proteostasis deficiencies.