Internexin

Alpha-internexin has a homologous central rod domain of approximately 310 amino acid residues that form a highly conserved alpha helical region. The central rod domain is responsible for coiled-coil structure and is flanked by an amino terminal head region and a carboxy terminal tail.[2] This rod domain is also involved in the 10 nm filament assembly structure. The head and tail regions contain segments that are highly homologous to the NF-M’s structure.[1] The head region is highly basic and contains many serine and threonine polymers while the tail region has distinct sequence motifs like a glutamate rich region.[3] The alpha domain is composed of heptad repeats of hydrophobic residues that aid the formation of a coiled coil structure.[3] The structure of Alpha-internexin is highly conserved between rats, mice and humans.[1]

Mixed neuron/glial cultures from p18 rat embryo brain stained with antibody to alpha-internexin which reveals, in red, neuronal processes and cell bodies. Cells were also labelled in green for Coronin 1a, a marker for microglia.

Alpha-internexin can form homopolymers, unlike the heteropolymer the neurofilaments form. This formation suggests that α-internexin and the three neurofilaments form separate filament systems.[4] Not only can alpha-internexin form homopolymers but it form a network of extended filaments in the absence of other intermediate filament proteins and efficiently co-assemble with any type IV or type III subunit, in vitro.[1] In Ching et al., a model of the intermediate filaments assembly is proposed. This model includes the following steps:

• Step 1: in the first step of IF assembly two parallel, unstaggered intermediate filament polypeptides chains form a dimer via their a-helical rod domains; these dimers can be either homodimers or heterodimers.
• Step 2: the dimers may associate laterally to form antiparallel, unstaggered tetramers or antiparallel, staggered tetramers.
• Step 3: the dimers may also associate longitudinally with a short head-to-tail overlap of the a-helical rod domains.
• Step 4: these lateral and longitudinal associations lead to the formation of protofibrils (octamers) and ultimately 10 nm intermediate filaments.[5]

The close connection between the neurofilament triplet proteins and α-internexin is quite obvious. α-internexin is functionally interdependent with the neurofilament triplet proteins.[4] If one genetically deletes NF-M and/or NF-H in mice, the transport and presence, in the axons of the Central Nervous System, of α-internexin will be drastically reduced. Not only are they functionally similar, the turnover rates are also similar among the four proteins.[4]

It is expressed in early development in the neuroblast along with α-internexin and peripherin. As development continues into neurons the neurofilament triplet proteins (NF-L: neurofilament low molecular mass, NF-M: neurofilament medium molecular mass, and NF-H: neurofilament high molecular mass) are expressed in increasing molecular mass order as α-internexin expression decreases.[3] In the neuroblast phase of development α-internexin is found in the neural tube and neural crest derived neuroblasts.

In adult cells, α-internexin is expressed abundantly in the central nervous system, in the cytoplasm of neurons, along with the neurofilament triplet proteins. They are expressed in a relatively fixed stoichiometric ratio to neurofilaments.[4]

Alpha-internexin is a brain and central nervous system filament that is involved in neuronal development and has been suggested to play a role in axonal outgrowth. Gefiltin and xefiltin, homologs of α-internexin in zebrafish and Xenopus laevis, respectively, are highly expressed during retinal growth and optic axon regeneration and therefore have aided the speculation that α-internexin and axonal outgrowth may be connected.[1] With this speculation, studies have been performed to develop a stronger bridge between the two. Through knockout studies using mice, the inhibition of α-internexin had no visible effect on development of the nervous system which suggests that axonal outgrowth is unaffected by α-internexin, however, the knockout study failed to rule out subtle differences that the protein may have caused.[4] Not only has α-internexin been linked to axonal outgrowth but it may regulate axonal stability or diameter through changes in filaments and their subunit composition.[1] Also, internexin could be involved in the maintenance or the formation of dendritic spines.[4] There have been many implications as to the function of α-internexin, but no concrete evidence currently exists to fully support or negate these speculations.

α-internexin has also been implicated in several degenerative diseases such as Alzheimer's disease, amyotrophic lateral sclerosis, dementia with Lewy bodies, Parkinson's disease, neuropathies, tropical spastic paraparesis and HTLV-1 associated myelopathy. In HTLV-1 myelopathy, Tax, transactivator expressed by HTLV-1, interacts with α-internexin in cell culture resulting in dramatic reduction in Tax transcactivation and intermediate filament formation.

• Neurofilaments
• Intermediate filament

• Interactions of internexin alpha
• alpha-internexin at the US National Library of Medicine Medical Subject Headings (MeSH)