Real-time imaging reveals defects of fast axonal transport induced by disorganization of intermediate filaments

Intermediate filament (IF) abnormalities frequently appear in neurodegenerative disorders, but how they may contribute to neuronal dysfunction remains unclear. Here, we examined the effects of IF disorganization on the fast axonal transport using time-lapse microscopy. We studied the axonal transport of mitochondria and lysosomes in cultured primary dorsal root ganglion (DRG) neurons derived from mice deficient for neurofilament light (NFL(-/-)), mice overexpressing peripherin (Per), and mice double transgenic Per;NFL(-/-). Unexpectedly, a net retrograde transport of mitochondria was detected in Per;NFL(-/-) neurons, opposite to the net anterograde transport of these organelles observed in wild-type (Wt), NFL(-/-), and Per neurons. A detailed analysis of the kinetic properties of mitochondrial movements revealed an increased frequency of retrograde movements and an increase of their velocity in Per;NFL(-/-) neurons compared to Wt, NFL(-/-), and Per neurons. We also noticed that the depletion of axonal neurofilaments (NFs) in NFL(-/-) and Per;NFL(-/-) neurons induced longer and more persistent movements of mitochondria and lysosomes in both directions, which suggests that the NF network hampers the traffic of these organelles. The finding that an up-regulation of peripherin in context of NFL deficiency can provoke a net retrograde transport of mitochondria is a phenomenon that may contribute to pathogenic changes in some neurodegenerative disorders with IF protein accumulations.