Peripherin Is a Subunit of Peripheral Nerve Neurofilaments: Implications for Differential Vulnerability of CNS and PNS Axons

Peripherin, a neuronal intermediate filament protein implicated in neurodegenerative disease, coexists with the neurofilament triplet proteins (NFL, NFM, and NFH) but has an unknown function. The earlier peak expression of peripherin 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 peripherin and neurofilament triplet form separate filament systems. Here, we demonstrate, however, that despite a postnatal decline in expression, peripherin is as abundant as the triplet in the adult PNS and exists in a relatively fixed stoichiometry with these subunits. Peripherin exhibits a distribution pattern identical to those of triplet proteins in sciatic axons and co-localizes with NFL on single neurofilament by immunogold electron microscopy. Peripherin also co-assembles into a single network of filaments containing NFL, NFM, NFH with and without α-internexin in quadrupleor quintuple-transfected SW13 vim (−) cells. Genetically deleting NFL in mice dramatically reduces peripherin content in sciatic axons. Moreover, peripherin mutations has been shown to disrupt the neurofilament network in transfected SW13 vim(−) cells. These data show that peripherin and the neurofilament proteins are functionally interdependent. The results strongly support the view that rather than forming an independent structure, peripherin is a subunit of neurofilaments in the adult PNS. Our findings provide a basis for its close relationship with neurofilaments in PNS diseases associated with neurofilament accumulation. Address correspondence to: Aidong Yuan, M.D., Ph.D. or Ralph A. Nixon, M.D., Ph.D., Center for Dementia Research, Nathan Kline Institute, New York University School of Medicine, 140 Old Orangeburg Rd., Orangeburg, NY 10962, Tel.: (845) 398-5450; Fax: (845) 398-5422, [email protected] or [email protected]. T. Sasaki’s present address: Department of Peripheral Nervous System, National Institute of Neuroscience, National Center of Neurology and Psychiatry, 4-1-1 Ogawa-higashi, Kodaira, Tokyo 187-8502, Japan. Author contributions: A.Y. designed research; A.Y., T.S., A.K., and C.M.P performed research; A.Y., M.V.R, R.K.L, J-P.J. and R.A.N. analyzed data; A.Y. and R.A.N. wrote the paper. No conflict of interest NIH Public Access Author Manuscript J Neurosci. Author manuscript; available in PMC 2012 December 20. Published in final edited form as: J Neurosci. 2012 June 20; 32(25): 8501–8508. doi:10.1523/JNEUROSCI.1081-12.2012. N IH PA Athor M anscript N IH PA Athor M anscript N IH PA Athor M anscript