TDP-43 in ALS/FTLD studied by a novel aggregate extraction method

Accumulation of abnormally phosphorylated TDP-43 (pTDP-43) is the main pathological finding characterizing affected neurons in most patients with amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD). At least four different subtypes of FTLD-TDP have been described, based on the morphology and neuroanatomical distribution of pathological TDP-43 accumulations. To understand the molecular basis of this heterogeneity that correlates with clinical presentations, we developed SarkoSpin, a new method for the biochemical isolation of pathological TDP-43 from complex tissues. Using postmortem samples of 79 patients and controls, we show that SarkoSpin allows the physical separation of pTDP-43 from ~99.8% of total proteins, including the extreme bulk of physiological TDP-43. Pathological TDP-43 extracted from different disease subtypes forms large and buoyant assemblies of distinct densities and 3-dimentional shapes that correlate with specific neuropathological classifications.