TDP-43 mislocalization drives neurofilament changes in a novel model of TDP-43 proteinopathy

ABSTRACT Mislocalization of the TAR DNA-binding protein 43 (TDP-43; encoded by TARDBP) from nucleus to cytoplasm is a common feature neurodegenerative conditions such as amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD). The downstream in vivo cellular effects this mislocalization are not well understood. To investigate impact mislocalized TDP-43 on neuronal cell bodies, axons axonal terminals, we utilized mouse visual system create new model proteinopathy. Mouse (C57BL/6J) retinal ganglion cells (RGCs) were transduced with GFP-tagged human wild-type (hTDP-WT-GFP) mutation nuclear localization sequence (hTDP-?NLS-GFP), cause mislocalization, ?60% transduction efficiency achieved. Expression both hTDP-WT-GFP hTDP-?NLS-GFP resulted changes neurofilament expression, cytoplasmic being associated significantly (P<0.05) increased heavy expression soma, forms altered leading decreased numbers neurofilament-positive within optic nerve. Alterations proteins microglial density nerve retina. Furthermore, was significant increase pre-synaptic input into RGCs current study has developed that allows detailed examination alterations will contribute knowledge TDP-43-mediated degeneration.