Article abstract
Nature Cell Biology 6, 595 - 608 (2004)
Published online: 20 June 2004 | doi:10.1038/ncb1139
A NUDEL-dependent mechanism of neurofilament assembly regulates the integrity of CNS neurons
Minh Dang Nguyen1,2, Tianzhi Shu1, Kamon Sanada1, Roxanne C. Larivière2,3, Huang-Chun Tseng1, Sang Ki Park1, Jean-Pierre Julien2,3 & Li-Huei Tsai1
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.
- Department of Pathology, Harvard Medical School and Howard Hughes Medical Institute, 77 Avenue Louis Pasteur, New Research Building, Room 856-8, MA 02115, USA.
- Centre for Research in Neuroscience, The Montreal General Hospital Research Institute, 1650 Cedar Avenue, Montréal, Québec, H3G 1A4, Canada.
- Present address: CHUL Research Center, Department of Anatomy and Physiology, Laval University, 2705 Boulevard Laurier, Sainte-Foy, Québec, G1V 4G2, Canada.
Correspondence to: Minh Dang Nguyen1,2 e-mail: minh-dang_nguyen@hms.harvard.edu
Correspondence to: Li-Huei Tsai1 e-mail: li-huei_tsai@hms.harvard.edu
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