Mislocalisation of TDP-43 to the cytoplasm of either neurons or oligodendrocytes causes axonopathy and dysmyelination

Abstract

Neurons with large, myelinated axons are vulnerable to degeneration across the amyotrophic lateral sclerosis (ALS) frontotemporal dementia (FTD) disease spectrum. The defining molecular pathology of this spectrum is mislocalisation of the RNA binding protein TDP-43 from the nucleus to the cytoplasm. Even though cytoplasmic TDP-43 is prevalent in neurons and oligodendrocytes, how these molecular pathologies contribute to neurodegeneration remains unclear. Here we developed humanised zebrafish in which we restricted TDP-43 to the cytoplasm of either neurons or oligodendrocytes. Cytoplasmic TDP-43 restricted to neurons led to a severe axonopathy, with extreme distal axonal swelling and reduced myelination. Axonopathy was mirrored by cell type specific loss of TDP-43 function from neurons, pointing to loss of function, rather than a toxic gain of function of mislocalised TDP-43, as driving this phenotype. Preventing oligodendrocyte differentiation and myelination when TDP-43 was mislocalised in neurons exacerbated axonopathy, indicating that oligodendrocytes limit neurodegeneration. Indeed, when TDP-43 was mislocalised to the cytoplasm of oligodendrocytes this also led to axonopathy and reduced myelination, pointing to complex contributions of neurons and oligodendrocytes to neurodegeneration.