TDP-43 and FUS/TLS are RNA/DNA-binding proteins with structural and functional similarities, and their abnormal aggregation is linked to amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD). These proteins are involved in RNA processing and have been identified as causative factors in both sporadic and familial forms of ALS and FTLD. TDP-43 is primarily nuclear under normal conditions but can mislocalize to the cytoplasm, leading to neurodegeneration. FUS/TLS is also mainly nuclear, but its mislocalization to the cytoplasm is associated with neurodegenerative processes. Both proteins are involved in multiple steps of RNA processing, including transcription, splicing, transport, and translation. They also play roles in microRNA processing and the regulation of RNA subcellular localization, translation, and degradation. TDP-43 and FUS/TLS are involved in the formation of RNA stress granules and are essential for the maintenance of genome stability. Mutations in these proteins can lead to the accumulation of cytoplasmic inclusions and are associated with various neurodegenerative diseases. The pathogenesis of these diseases involves the mislocalization and aggregation of TDP-43 and FUS/TLS, which disrupts normal RNA processing and leads to neuronal dysfunction. Understanding the roles of TDP-43 and FUS/TLS in RNA processing and neurodegeneration is crucial for developing therapeutic strategies for these diseases.TDP-43 and FUS/TLS are RNA/DNA-binding proteins with structural and functional similarities, and their abnormal aggregation is linked to amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD). These proteins are involved in RNA processing and have been identified as causative factors in both sporadic and familial forms of ALS and FTLD. TDP-43 is primarily nuclear under normal conditions but can mislocalize to the cytoplasm, leading to neurodegeneration. FUS/TLS is also mainly nuclear, but its mislocalization to the cytoplasm is associated with neurodegenerative processes. Both proteins are involved in multiple steps of RNA processing, including transcription, splicing, transport, and translation. They also play roles in microRNA processing and the regulation of RNA subcellular localization, translation, and degradation. TDP-43 and FUS/TLS are involved in the formation of RNA stress granules and are essential for the maintenance of genome stability. Mutations in these proteins can lead to the accumulation of cytoplasmic inclusions and are associated with various neurodegenerative diseases. The pathogenesis of these diseases involves the mislocalization and aggregation of TDP-43 and FUS/TLS, which disrupts normal RNA processing and leads to neuronal dysfunction. Understanding the roles of TDP-43 and FUS/TLS in RNA processing and neurodegeneration is crucial for developing therapeutic strategies for these diseases.