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A NUDEL-dependent mechanism of neurofilament assembly regulates the integrity of CNS neurons

Nature Cell Biology volume 6, pages 595–608 (2004)Cite this article

Abstract

The cytoskeleton controls the architecture and survival of central nervous system (CNS) neurons by maintaining the stability of axons and dendrites. Although neurofilaments (NFs) constitute the main cytoskeletal network in these structures, the mechanism that underlies subunit incorporation into filaments remains a mystery. Here we report that NUDEL, a mammalian homologue of the Aspergillus nidulans nuclear distribution molecule NudE, is important for NF assembly, transport and neuronal integrity. NUDEL facilitates the polymerization of NFs through a direct interaction with the NF light subunit (NF-L). Knockdown of NUDEL by RNA interference (RNAi) in a neuroblastoma cell line, primary cortical neurons or post-natal mouse brain destabilizes NF-L and alters the homeostasis of NFs. This results in NF abnormalities and morphological changes reminiscent of neurodegeneration. Furthermore, variations in levels of NUDEL correlate with disease progression and NF defects in a mouse model of neurodegeneration. Thus, NUDEL contributes to the integrity of CNS neurons by regulating NF assembly.

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Figure 1: NUDEL interacts directly with NF-L and indirectly with NF-H.
Figure 2: NUDEL associates with NF structures in vivo.
Figure 5: Genetic knockdown of NUDEL in primary cortical neurons causes cell-shape abnormalities.
Figure 3: NUDEL facilitates NF polymerization in vitro, but does not form polymers with NF proteins.
Figure 4: Silencing expression of NUDEL in CAD cells causes NF abnormalities.
Figure 6: Genetic knockdown of NUDEL in the post-natal mouse brain disrupts NF homeostasis.
Figure 7: Downregulation of NUDEL coincides with NF defects during in vivo neurodegeneration.
Figure 8: Roles for NUDEL in the biology of NFs and neuronal integrity.

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Acknowledgements

The technical help of P. Hince, S. Millecamps and M. Ericsson is gratefully acknowledged. We are grateful to J. Robertson for the CMV–NF-L and CMV–NF-H plasmids; M. Elhers and R. Huganir for the pC86–NF-L–rod plasmid; T. Shea for the NF-M–GFP plasmid; A. Musacchio for purified NUDEL-CC; D.L. Price and D.W. Cleveland for the kind gift of SOD1G37R mice (line 29); J. Colhberg and U. Aebi for helpful advice on NF polymerization; Z. Xie and R. Ayala for discussions; and M.-T. A. Nguyen, L. Moy, J. Cruz and B. Samuels for critical reading of the manuscript. This work was supported by grants from the National Institutes of Health (for J.-P.J. and L.-H.T.) and the Howard Hughes Medical Institute (for L.-H. T.) M.D.N. held a KM Hunter/Canadian Institute of Health Research PhD scholarship and is a recipient of a long-term fellowship from the Human Frontier Science Program Organization. K.S. holds a Japan Society for the Promotion of Science postdoctoral fellowship for research abroad. R.L. was a recipient of a PhD scholarship from the Fonds de la Recherche de la Santé du Québec. S.-K.P. is a fellow of the Taplin Foundation.

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  1. Roxanne C. Larivière & Jean-Pierre Julien

    Present address: CHUL Research Center, Department of Anatomy and Physiology, Laval University, 2705 Boulevard Laurier, Sainte-Foy, Québec, G1V 4G2, Canada

Authors and Affiliations

  1. Department of Pathology, Harvard Medical School and Howard Hughes Medical Institute, 77 Avenue Louis Pasteur, New Research Building, Room 856-8, 02115, MA, USA

    Minh Dang Nguyen, Tianzhi Shu, Kamon Sanada, Huang-Chun Tseng, Sang Ki Park & Li-Huei Tsai

  2. Centre for Research in Neuroscience, The Montreal General Hospital Research Institute, 1650 Cedar Avenue, Montréal, H3G 1A4, Québec, Canada

    Minh Dang Nguyen, Roxanne C. Larivière & Jean-Pierre Julien

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Nguyen, M., Shu, T., Sanada, K. et al. A NUDEL-dependent mechanism of neurofilament assembly regulates the integrity of CNS neurons. Nat Cell Biol 6, 595–608 (2004). https://doi.org/10.1038/ncb1139

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