Identifying the components of TDP-43 phase-separated granules using proximity labeling
Shan Lu1,2, Haiyang Yu1, Cong Chen1, Fatima Gasset-Rosa1, John R Yates III2, Sandrine Da Cruz1 and Don W Cleveland1
1Ludwig Institute for Cancer Research, Department of Medicine and Neuroscience, University of California, San Diego, La Jolla, CA 92093, United States; 2Department of Chemical Physiology and Molecular and Cellular Molecular Biology, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, California 92037, United States
TDP-43 pathology (the nuclear clearance of TDP-43 and its re-accumulation in pathological cytoplasmic inclusions) has been found in >90% of ALS patients and about half of patients with frontotemporal dementia (FTD). To identify the biological pathway(s) that may act to generate this pathology, proximity labeling coupled with quantitative mass spectrometry has been used to identify the proteins that specifically associate with TDP-43 phase-separated granules compared to the normal, diffusely localized, soluble TDP-43. Consistent with its well-known role in pre-mRNA maturation and splicing, the binding partners of nuclear TDP-43 are a closely interacting network of nuclear mRNA processing proteins. In contrast, we identify 42 interactors of cytoplasmic, apparently phase separated TDP-43. This study provides an initial picture of the proteins that can associate with TDP-43 when it de-mixes and identifies novel potential mechanisms that underlie TDP-43 aggregation in ALS/FTD.