| Abstract No.: | A-C1118 |
| Country: | Canada |
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| Title: | REAL-TIME IMAGING REVEALS DEFECTS OF FAST AXONAL TRANSPORT INDUCED BY DISORGANIZATION OF INTERMEDIATE FILAMENTS |
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| Authors/Affiliations: | 1 Rodolphe Perrot*; 1 Jean-Pierre Julien;
1 Department of Anatomy and Physiology, Laval University, Research Centre of CHUL, Quebec, QC, Canada
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| Content: | Many human neurodegenerative disorders, including amyotrophic lateral sclerosis, Parkinson’s disease, Charcot-Marie-Tooth and giant axonal neuropathy, are characterized by the abnormal accumulations of intermediate filaments (IF). Several evidences suggest that disorganization of the neuronal IF network may be directly involved in neurodegeneration. However, the exact molecular mechanisms underlying the deleterious effects of IF disorganization are still unclear. Our general hypothesis is that changes in the organization of IF can alter the fast axonal transport machinery either through levels of motor proteins or block of cargoe movement. The axonal transport of organelles like mitochondria and lysosomes may be impaired and play a role in the neurodegeneration. To test this hypothesis, we analyzed by time-lapse imaging the mitochondrial and the lysosomal axonal transports in cultured dorsal root ganglion neurons from different mouse models with various abnormalities of the endogenous IF network. Among these models are NFL knockout mice (NFL-/- mice), which are characterized by the absence of axonal neurofilaments, mice overexpressing peripherin (Per mice) that develop a motor neuron disease characterized by the presence of IF inclusions, and finally Per;NFL-/- mice in which the onset of peripherin-mediated disease is precipitated. We observed that the depletion of axonal neurofilaments in NFL-/- and Per;NFL-/- neurons induced longer and more persistent movements of mitochondria and lysosomes in both anterograde and retrograde directions, indicating that the endogenous neurofilament network tends to slow down fast axonal transport. In contrast, the overexpression of peripherin alone did not induce major alterations of fast axonal transport. Unexpectedly, we detected a net retrograde transport of mitochondria in Per;NFL-/- neurons in contrast to a net anterograde transport of these organelles in Wt, NFL-/- and Per neurons. This could potentially lead to a depletion of axonal mitochondria in distal regions of Per;NFL-/- peripheral nerves. Finally, a protein analysis performed on proximal to distal segments of sciatic nerve reveals a decrease content of dynein in distal segments from 1-year-old Per;NFL-/- mice. These results indicate that disorganization of the endogenous IF network can affect the distribution of molecular motors and perturb fast axonal transport. These defects could contribute to the neurodegenerative process in pathologies with IF abnormalities. |
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