Alpha-internexin is structurally and functionally associated with the neurofilament triplet proteins in the mature CNS.

Abstract

Alpha-internexin, a neuronal intermediate filament protein implicated in neurodegenerative disease, coexists with the neurofilament (NF) triplet proteins (NF-L, NF-M, and NF-H) but has an unknown function. The earlier peak expression of alpha-internexin than the triplet during brain development and its ability to form homopolymers, unlike the triplet, which are obligate heteropolymers, have supported a widely held view that alpha-internexin and neurofilament triplet form separate filament systems. Here, we demonstrate, however, that despite a postnatal decline in expression, alpha-internexin is as abundant as the triplet in the adult CNS and exists in a relatively fixed stoichiometry with these subunits. Alpha-internexin exhibits transport and turnover rates identical to those of triplet proteins in optic axons and colocalizes with NF-M on single neurofilaments by immunogold electron microscopy. Alpha-internexin also coassembles with all three neurofilament proteins into a single network of filaments in quadruple-transfected SW13vim(-) cells. Genetically deleting NF-M alone or together with NF-H in mice dramatically reduces alpha-internexin transport and content in axons throughout the CNS. Moreover, deleting alpha-internexin potentiates the effects of NF-M deletion on NF-H and NF-L transport. Finally, overexpressing a NF-H-LacZ fusion protein in mice induces alpha-internexin and neurofilament triplet to aggregate in neuronal perikarya and greatly reduces their transport and content selectively in axons. Our data show that alpha-internexin and the neurofilament proteins are functionally interdependent. The results strongly support the view that alpha-internexin is a fourth subunit of neurofilaments in the adult CNS, providing a basis for its close relationship with neurofilaments in CNS diseases associated with neurofilament accumulation.

• Authors: Aidong Yuan, Mala V Rao, Takahiro Sasaki, Yuanxin Chen, Asok Kumar, Veeranna, Ronald K H Liem, Joel Eyer, Alan C Peterson, Jean-Pierre Julien, Ralph A Nixon
• Journal: The Journal of neuroscience : the official journal of the Society for Neuroscience (J Neurosci) Vol. 26 Issue 39 Pg. 10006-19 (Sep 27 2006) ISSN: 1529-2401 [Electronic] United States
• PMID: 17005864 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)

Chemical References

• Intermediate Filament Proteins
• Multiprotein Complexes
• Neurofilament Proteins
• Recombinant Fusion Proteins
• alpha-internexin
• neurofilament protein L
• neurofilament protein H
• neurofilament protein M

Topics

• Animals
• Axons (chemistry, ultrastructure)
• Crosses, Genetic
• Female
• Intermediate Filament Proteins (analysis, deficiency, genetics, physiology, ultrastructure)
• Intermediate Filaments (chemistry, ultrastructure)
• Male
• Mice
• Mice, Inbred C57BL
• Mice, Knockout
• Microscopy, Confocal
• Microscopy, Fluorescence
• Microscopy, Immunoelectron
• Multiprotein Complexes
• Nerve Degeneration (metabolism, pathology)
• Neurofilament Proteins (analysis, deficiency, genetics, physiology, ultrastructure)
• Protein Interaction Mapping
• Protein Transport
• Rats
• Recombinant Fusion Proteins (analysis, physiology)
• Retinal Ganglion Cells (chemistry, ultrastructure)
• Spinal Cord (chemistry, ultrastructure)
• Structure-Activity Relationship
• Transfection