Fig. 6. An autophagy-centric model of TDP43 pathology.

(A) TDP43 (red) primarily localizes to the nucleus in healthy neurons. RNA misprocessing, genetic mutations, or environmental factors may trigger TDP43 nuclear egress and cytosolic accumulation. (B) Increasing amounts of mislocalized TDP43 leads to the accumulation of mislocalized TDP43 in autophagosomes and lysosomes. (C) Increased burden of mislocalized TDP43 leads to the loss of TDP43 splicing activity and cytosolic TDP43 fibrilization, as seen in ALS, FTD, and other TDP43 proteinopathies. (D) TDP43, LC3B, and LAMP1 immunohistochemistry (left) and immunofluorescence (right) of ALS patient tissue. Scale bars, 20μm (left) and 5μm (right). (E) Restoring TDP43 nuclear localization has pharmacotherapeutic potential to prevent TDP43 pathology.