[Neuropathology of TDP-43 proteinopathy]

TAR DNA-binding protein 43 (TDP-43) is a member of the heterogeneous nuclear ribonucleoprotein family, a group of proteins involved in pre-mRNA splicing, RNA stability, transport, and metabolism. TDP-43 was identified as the major component of pathological protein aggregates present in a subset of frontotemporal lobar degeneration (FTLD), which is now referred to as FTLD-TDP. TDP-43 is also deposited in the sporadic form of amyotrophic lateral sclerosis (ALS) as well as in familial ALS with mutations in the gene for TDP-43. Based on histopathology, the accumulation of TDP-43 in the brain cortex is classified into 4 types, type A through D, depending on the forms of TDP-43 accumulation in the cerebral cortex. Type A pathology is frequently observed in frontotemporal dementia and progressive non-fluent aphasia. Type B pathology occurs in FTLD with ALS and ALS with lesions that extend to the cerebral cortex. Type C pathology is associated with semantic dementia. In FTLD and ALS, TDP-43 forms insoluble aggregates and gets phosphorylated, ubiquitinated, and fragmented. The fragment patterns on immunoblot of brain homogenates correspond to each histopathological type, indicating their relevance to the pathogenesis of TDP-43 proteinopathy.