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

Nguyen MD, Shu T, Sanada K, Lariviere RC, Tseng HC, Park SK, Julien JP and Tsai LH
Source: Nat Cell Biol
Publication Date: (2004)
Issue: 6(7): 595-608
Research Area:
Cells used in publication:
Neuron, cortical, mouse
Species: mouse
Tissue Origin: brain
NUDEL or neurofilament subunit NF-L were knocked down in mouse primary cortical neurons by nucleofection with siRNA expressing plasmids. A GFP fusion of neurofilament subunit NF-M was expressed in primary cortical neurons to visualize neurofilaments. A GFP expression plasmid was cotransfected into primary neurons to visualize cell shape.
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.