The basis of clinicopathological heterogeneity in TDP-43 proteinopathy.

Transactive response DNA-binding protein 43 kDa (TDP-43) was identified as a major disease-associated component in the brain of patients with amyotrophic lateral sclerosis (ALS), as well as the largest subset of patients with frontotemporal lobar degeneration with ubiquitinated inclusions (FTLD-U), which characteristically exhibits cytoplasmic inclusions that are positive for ubiquitin but negative for tau and α-synuclein. TDP-43 pathology occurs in distinct brain regions, involves disparate brain networks, and features accumulation of misfolded proteins in various cell types and in different neuroanatomical regions. The clinical phenotypes of ALS and FTLD-TDP (FTLD with abnormal intracellular accumulations of TDP-43) correlate with characteristic distribution patterns of the underlying pathology across specific brain regions with disease progression. Recent studies support the idea that pathological protein spreads from neuron to neuron via axonal transport in a hierarchical manner. However, little is known to date about the basis of the selective cellular and regional vulnerability, although the information would have important implications for the development of targeted and personalized therapies. Here, we aim to summarize recent advances in the neuropathology, genetics and animal models of TDP-43 proteinopathy, and their relationship to clinical phenotypes for the underlying selective neuronal and regional susceptibilities. Finally, we attempt to integrate these findings into the emerging picture of TDP-43 proteinopathy, and to highlight key issues for future therapy and research.