23 Jun 2012

It is a well-established trio: the light, medium, and heavy chains of neurofilament assemble together to form axonal girders. But in the June 22 Journal of Neuroscience, researchers from the Nathan Kline Institute in Orangeburg, New York, report that peripherin joins in as a fourth member of the filaments. Senior author Ralph Nixon and colleagues suggest that this lineup, which is specific to peripheral nerves, could help explain why these neurons are susceptible to certain diseases, while other conditions affect the central nervous system. For example, peripherin mutations show up in some cases of amyotrophic lateral sclerosis (ALS) (Gros-Louis et al., 2004; Leung et al., 2004; Corrado et al., 2011).

Neurofilaments are members of a family of proteins called intermediate filaments. Along with the narrower actin and the wider microtubules, they make up the three components of the cytoskeleton. Scientists once viewed intermediate filaments as simple struts, but that interpretation is changing, Nixon said. Neurofilaments act as docking sites for organelles and molecular motors, and thus influence cellular function, he told Alzforum. It is rather like discovering the struts of your house were also flipping on the lights or cooking dinner. “Neurofilaments have been under the radar for a while now, and I think they may re-emerge as much more intriguing [structures],” Nixon predicted. In the current work, Nixon and first author Aidong Yuan challenge another long-held assumption about peripherin: its loner status.

Researchers had assumed that peripherin made its own assemblies, since it forms homopolymers when transfected into cells devoid of any other intermediate filaments (Cui et al., 1995). But scientists thought the same thing about α-internexin, peripherin’s central nervous system counterpart, yet Yuan and Nixon found that α-internexin complexes with neurofilament (Yuan et al., 2006). Could peripherin do the same? They ran the protein through a set of tests to determine if it also joins up with neurofilament.

First, the researchers asked if peripherin is abundant enough to be a regular neurofilament component. Yuan determined there were about one-third as many peripherin molecules as there were neurofilament light chain proteins in mouse sciatic axons. The light chain is among the most abundant proteins in these cells, so the results indicate there is enough peripherin to serve as a full-fledged neurofilament subunit, not just an occasional accessory, Nixon said. The researchers calculated the makeup of neurofilaments from sciatic nerve to have a ratio of four light chain, two medium, one heavy, to one peripherin.

Second, the researchers tested if peripherin and neurofilament are found together. Electron micrographs of sciatic nerves confirmed they are. Yuan also transfected the three neurofilament components plus peripherin into a human adrenal carcinoma line, SW13, which lacked its own intermediate filaments. All four lined up together under fluorescence microscopy, suggesting that they form a complex, though that may be open to interpretation. “The results can also be explained by the presence of parallel peripherin fibers that co-localize with neurofilament,” noted Cristian Droppelmann of the University of Western Ontario in London, Canada, in an e-mail to ARF. “However, the results are strong enough to suggest that the assembly of peripherin as a fourth subunit of neurofilament is highly plausible.”

Two flavors of neurofilament—one with peripherin and the other with α-internexin—could help explain why peripheral nerves and central nerves succumb to different diseases, the authors wrote. Each version likely plays a different cellular role and recruits different organelles, Nixon suggested, although the precise tasks are still under investigation in his lab. Therefore, insults to α-internexin-neurofilament and any associated proteins would likely cause central nervous system degeneration (Cairns et al., 2004). Alterations to the peripherin-neurofilament system would lead to disorders such as ALS, where scientists have discovered that peripherin mutations and neurofilament aggregates make up part of the pathology (Strong et al., 2001). “Neurofilaments are essential, and a target of genetic mischief that affects the central nervous system and peripheral nervous system,” Nixon said.—Amber Dance

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References

Paper Citations

1. Gros-Louis F, Larivière R, Gowing G, Laurent S, Camu W, Bouchard JP, Meininger V, Rouleau GA, Julien JP. A frameshift deletion in peripherin gene associated with amyotrophic lateral sclerosis. J Biol Chem. 2004 Oct 29;279(44):45951-6. PubMed.
2. Leung CL, He CZ, Kaufmann P, Chin SS, Naini A, Liem RK, Mitsumoto H, Hays AP. A pathogenic peripherin gene mutation in a patient with amyotrophic lateral sclerosis. Brain Pathol. 2004 Jul;14(3):290-6. PubMed.
3. Corrado L, Carlomagno Y, Falasco L, Mellone S, Godi M, Cova E, Cereda C, Testa L, Mazzini L, D'Alfonso S. A novel peripherin gene (PRPH) mutation identified in one sporadic amyotrophic lateral sclerosis patient. Neurobiol Aging. 2011 Mar;32(3):552.e1-6. PubMed.
4. Cui C, Stambrook PJ, Parysek LM. Peripherin assembles into homopolymers in SW13 cells. J Cell Sci. 1995 Oct;108 ( Pt 10):3279-84. PubMed.
5. Yuan A, Rao MV, Sasaki T, Chen Y, Kumar A, Veeranna, Liem RK, Eyer J, Peterson AC, Julien JP, Nixon RA. Alpha-internexin is structurally and functionally associated with the neurofilament triplet proteins in the mature CNS. J Neurosci. 2006 Sep 27;26(39):10006-19. PubMed.
6. Cairns NJ, Zhukareva V, Uryu K, Zhang B, Bigio E, Mackenzie IR, Gearing M, Duyckaerts C, Yokoo H, Nakazato Y, Jaros E, Perry RH, Lee VM, Trojanowski JQ. alpha-internexin is present in the pathological inclusions of neuronal intermediate filament inclusion disease. Am J Pathol. 2004 Jun;164(6):2153-61. PubMed.
7. Strong MJ, Strong WL, Jaffe H, Traggert B, Sopper MM, Pant HC. Phosphorylation state of the native high-molecular-weight neurofilament subunit protein from cervical spinal cord in sporadic amyotrophic lateral sclerosis. J Neurochem. 2001 Mar;76(5):1315-25. PubMed.

Further Reading

Papers

1. Liem RK, Messing A. Dysfunctions of neuronal and glial intermediate filaments in disease. J Clin Invest. 2009 Jul;119(7):1814-24. PubMed.
2. Perrot R, Julien JP. Real-time imaging reveals defects of fast axonal transport induced by disorganization of intermediate filaments. FASEB J. 2009 Sep;23(9):3213-25. PubMed.
3. Millecamps S, Robertson J, Lariviere R, Mallet J, Julien JP. Defective axonal transport of neurofilament proteins in neurons overexpressing peripherin. J Neurochem. 2006 Aug;98(3):926-38. PubMed.

News

1. ALS Research: More TDP-43, and Peripherin No Longer in Periphery? 7 Mar 2008
2. Neurofilaments May Be Essential to Some Tauopathies 22 Nov 2002