Waldron, F. M.; Langerova, T.; Read, F. L.; Spence, H.; Hanna, K.; Roberts, K.; Pattle, S. B.; Gregory, J. M.

A recently developed TDP-43 RNA aptamer (TDP-43APT) with greater sensitivity and specificity for detecting pathological TDP-43, compared to currently available antibodies, has revealed novel pathologies in ALS, including early nuclear aggregation preceding disease symptoms. Moreover, whilst ALS has traditionally been considered a disease of the central nervous system (CNS), non-CNS manifestations of disease are gaining increasing awareness. Employing an antibody approach to detect pathologically phosphorylated TDP-43, we previously uncovered pre-symptomatic, systemic TDP-43 pathology in archived non-CNS tissue, taken during life. Here, using two recently developed tools, (i) TDP-43APT to identify pathological TDP-43, and (ii) in situ hybridisation probes directed to a splice target of TDP-43 (Stathmin-2) to demonstrate concurrent loss of TDP-43 function, we re-examined non-CNS tissues from a variety of organ systems from this cohort of ante-mortem tissue taken from people who went on to develop ALS. Amongst non-CNS organs with evidence of pathological TDP-43 aggregation, and concurrent TDP-43 loss-of-function, occurring prior to motor symptom onset, were colon, skin, muscle, blood vessels, gallbladder, and lymph nodes. Cell types affected include sebocytes, endothelial cells, peripheral neuronal cells, dendritic cells, chondrocytes - all cells with a shared cell linage from the neural crest, implying a neurodevelopmentally-defined cell-type specific predisposition to TDP-43 pathology. This cell-type predisposition, along with TDP-43 pathology identified in tissue mobile, circulating inflammatory cells (T-cells and macrophages) may help to guide early, pre-symptomatic peripheral biopsy and biomarker development. Our findings extend the number of tissue and cell types with pathological TDP-43 aggregation outside of the CNS prior to motor symptoms, showing this is a common feature of ALS, affecting a number of organ systems that are readily accessible for biopsy. We propose that skin and gastro-intestinal tract tissues provide the most promising potential for ease of biopsy, with potential applications for ALS diagnosis and monitoring prior to motor symptom emergence amongst general and at-risk populations.