A NUDEL-dependent mechanism of neurofilament assembly regulates the integrity of CNS neurons.
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.
Nguyen
Minh Dang
MD
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
Shu
Tianzhi
T
Sanada
Kamon
K
Larivière
Roxanne C
RC
Tseng
Huang-Chun
HC
Park
Sang Ki
SK
Julien
Jean-Pierre
JP
Tsai
Li-Huei
LH
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
D002352:Carrier Proteins; C486015:Ndel1 protein, mouse; D016900:Neurofilament Proteins; D011108:Polymers; C044882:neurofilament protein L