The Role of TDP-43 in Neurodegenerative Disease

Nelson et al. describe a recently recognized brain disorder that mimics the clinical features of Alzheimer’s disease: Limbic-predominant Age-related TDP-43 Encephalopathy (LATE). They review the literature and present consensus-based recommendations of an international, multidisciplinary working group, providing guidelines for diagnosis and staging of LATE neuropathological changes.

Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease that is familial in 10% of cases. We have identified a missense mutation in the gene encoding fused in sarcoma (FUS) in a British kindred, linked to ALS6. In a survey of 197 familial ALS index cases, we identified two further missense mutations in eight families. Postmortem analysis of three cases with FUS mutations showed FUS-immunoreactive cytoplasmic inclusions and predominantly lower motor neuron degeneration. Cellular expression studies revealed aberrant localization of mutant FUS protein. FUS is involved in the regulation of transcription and RNA splicing and transport, and it has functional homology to another ALS gene, TARDBP, which suggests that a common mechanism may underlie motor neuron degeneration.

The cytoplasmic mislocalization and aggregation of TAR DNA-binding protein-43 (TDP-43) is a common histopathological hallmark of the amyotrophic lateral sclerosis and frontotemporal dementia disease spectrum (ALS/FTD). However, the composition of aggregates and their contribution to the disease process remain unknown. Here, we used proximity-dependent biotin identification (BioID) to interrogate the interactome of detergent-insoluble TDP-43 aggregates, and found them enriched for components of the nuclear pore complex (NPC) and nucleocytoplasmic transport machinery. Aggregated and disease-linked mutant TDP-43 triggered the sequestration and/or mislocalization of nucleoporins (Nups) and transport factors (TFs), and interfered with nuclear protein import and RNA export in mouse primary cortical neurons, human fibroblasts, and iPSC-derived neurons. Nuclear pore pathology is present in brain tissue from sporadic ALS cases (sALS) and those with genetic mutations in TARDBP (TDP-ALS) and C9orf72 (C9-ALS). Our data strongly implicate TDP-43-mediated nucleocytoplasmic transport defects as a common disease mechanism in ALS/FTD.