title: A NUDEL-dependent mechanism of neurofilament assembly regulates the integrity of CNS neurons.
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.
authors.affiliation: Department of Pathology, Harvard Medical School and Howard Hughes Medical Institute, 77 Avenue Louis Pasteur, New Research Building, Room 856-8, MA 02115, USA. minh-dang_nguyen@hms.harvard.edu
authors.forename: Minh Dang
authors.initials: MD
authors.lastname: Nguyen
authors.forename: Tianzhi
authors.initials: T
authors.lastname: Shu
authors.forename: Kamon
authors.initials: K
authors.lastname: Sanada
authors.forename: Roxanne C
authors.initials: RC
authors.lastname: Larivière
authors.forename: Huang-Chun
authors.initials: HC
authors.lastname: Tseng
authors.forename: Sang Ki
authors.initials: SK
authors.lastname: Park
authors.forename: Jean-Pierre
authors.initials: JP
authors.lastname: Julien
authors.forename: Li-Huei
authors.initials: LH
authors.lastname: Tsai
mesh_terms: D008841:Actin Cytoskeleton / Q000378:metabolism* / Q000648:ultrastructure; D000818:Animals; D000831:Animals, Newborn; D002352:Carrier Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D002454:Cell Differentiation / Q000235:genetics; D045744:Cell Line, Tumor; D002478:Cells, Cultured; D002490:Central Nervous System / Q000378:metabolism* / Q000648:ultrastructure; D004195:Disease Models, Animal; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008854:Microscopy, Electron; D019636:Neurodegenerative Diseases / Q000235:genetics / Q000378:metabolism / Q000503:physiopathology; D016900:Neurofilament Proteins / Q000096:biosynthesis*; D009474:Neurons / Q000378:metabolism* / Q000648:ultrastructure; D011108:Polymers / Q000378:metabolism; D021381:Protein Transport / Q000235:genetics; D034622:RNA Interference / Q000502:physiology
chemical_list: D002352:Carrier Proteins; C486015:Ndel1 protein, mouse; D016900:Neurofilament Proteins; D011108:Polymers; C044882:neurofilament protein L