alpha-Internexin is structurally and functionally associated with the neurofilament triplet proteins in the mature CNS

作者：Yuan Aidong^*; Rao Mala V; Sasaki Takahiro; Chen Yuanxin; Kumar Asok; Veeranna; Liem Ronald K H; Eyer Joel; Peterson Alan C; Julien Jean Pierre; Nixon Ralph A

来源：Journal of Neuroscience, 2006, 26(39): 10006-10019.

DOI：10.1523/JNEUROSCI.2580-06.2006

• alpha-internexin
• neurofilament
• intermediate filament
• neurofilament inclusion disease
• tropical spastic paraparesis
• axonal transport
• cytoskeleton

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-Hand 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.

• 出版日期2006-9-27