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Published 17 March 2003. doi:10.1083/jcb.200205027
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© The Rockefeller University Press, 0021-9525/2003/3/939 $5.00
The Journal of Cell Biology, Volume 160, Number 6, 939-949

Article

 A neurotoxic peripherin splice variant in a mouse model of ALS

Janice Robertson1,2, Mohammad M. Doroudchi3, Minh Dang Nguyen2, Heather D. Durham3, Michael J. Strong4, Gerry Shaw5, Jean-Pierre Julien1 and Walter E. Mushynski2

1 Centre for Research in Neurosciences, Research Institute of the McGill University Health Centre, McGill University, Montreal, Quebec, H3G 1A4, Canada
2 Department of Biochemistry, McGill University, Montreal, Quebec, H3G 1Y6, Canada
3 Montreal Neurological Institute, McGill University, Montreal, Quebec, H3A 2B4, Canada
4 Department of Clinical Neurological Sciences, The University of Western Ontario, London, Ontario, N6A 5A5, Canada
5 Department of Neuroscience, McKnight Brain Institute, University of Florida College of Medicine, Gainesville, FL 32611

Address correspondence to Janice Robertson, Centre for Research in Neurosciences, Research Institute of the McGill University Health Centre, McGill University, Montreal, Quebec, H3G 1A4, Canada. Tel.: (514) 934-1934 ext. 44203. Fax: (514) 934-8265. E-mail: janice.robertson{at}mcgill.ca

Peripherin, a neuronal intermediate filament (nIF) protein found associated with pathological aggregates in motor neurons of patients with amyotrophic lateral sclerosis (ALS) and of transgenic mice overexpressing mutant superoxide dismutase-1 (SOD1G37R), induces the selective degeneration of motor neurons when overexpressed in transgenic mice. Mouse peripherin is unique compared with other nIF proteins in that three peripherin isoforms are generated by alternative splicing. Here, the properties of the peripherin splice variants Per 58, Per 56, and Per 61 have been investigated in transfected cell lines, in primary motor neurons, and in transgenic mice overexpressing peripherin or overexpressing SOD1G37R. Of the three isoforms, Per 61 proved to be distinctly neurotoxic, being assembly incompetent and inducing degeneration of motor neurons in culture. Using isoform-specific antibodies, Per 61 expression was detected in motor neurons of SOD1G37R transgenic mice but not of control or peripherin transgenic mice. The Per 61 antibody also selectively labeled motor neurons and axonal spheroids in two cases of familial ALS and immunoprecipitated a higher molecular mass peripherin species from disease tissue. This evidence suggests that expression of neurotoxic splice variants of peripherin may contribute to the neurodegenerative mechanism in ALS.

Key Words: peripherin; isoforms; splicing; SOD1; ALS

* Abbreviations used in this paper: ALS, amyotrophic lateral sclerosis; DAB, 3,4-diaminobenzidine; IF, intermediate filament; NF-H, neurofilament heavy subunit; NF-L, neurofilament light subunit; NF-M, neurofilament medium subunit; nIF, neuronal IF; PVDF, polyvinyldifluoride; SOD1, superoxide dismutase-1.


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