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The Journal of Neuroscience, February 20, 2008, 28(8):1833-1840; doi:10.1523/JNEUROSCI.3222-07.2008

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Neurobiology of Disease
An Aggregate-Inducing Peripherin Isoform Generated through Intron Retention Is Upregulated in Amyotrophic Lateral Sclerosis and Associated with Disease Pathology

Shangxi Xiao,¹ Sonja Tjostheim,¹ Teresa Sanelli,¹ Jesse R. McLean,¹ Patrick Horne,¹ Yuxin Fan,² John Ravits,² Michael J. Strong,³ and Janice Robertson¹

¹Centre for Research in Neurodegenerative Diseases, University of Toronto, Toronto, Ontario, Canada M5S 3H2, ²Neurology Section, Neurogenomics Laboratory, Virginia Mason Medical Center, Benaroya Research Institute, Seattle, Washington 98101-2795, and ³Department of Clinical Neurological Sciences, The University of Western Ontario, London, Ontario, Canada N6A 5A5

Correspondence should be addressed to Dr. Janice Robertson, Centre for Research in Neurodegenerative Diseases, University of Toronto, Tanz Building, 6 Queen's Park Crescent West, Toronto, Ontario, Canada M5S 3H2. Email: jan.robertson{at}utoronto.ca

The neuronal intermediate filament protein peripherin is a component of ubiquitinated inclusions and of axonal spheroids in amyotrophic lateral sclerosis (ALS). Overexpression of peripherin causes motor neuron degeneration in transgenic mice and variations within the peripherin gene have been identified in ALS cases. We have shown previously the abnormal expression of a neurotoxic peripherin splice variant in transgenic mice expressing mutant superoxide dismutase-1. These findings indicated that abnormalities of peripherin splicing may occur in ALS. In the current study, peripherin splice variants were identified by reverse transcription-PCR of human neuronal RNA and comparisons in expression made between control and ALS spinal cord using Western blot analysis and immunocytochemistry. Using this approach we have identified a novel peripherin transcript retaining introns 3 and 4 that results in a 28 kDa splice isoform, designated Per 28. Using an antibody specific to Per 28, we show that this isoform is expressed at low stoichiometric levels from the peripherin gene, however causes peripherin aggregation when its expression is upregulated. Importantly we show an upregulation of Per 28 expression in ALS compared with controls, at both the mRNA and protein levels, and that Per 28 is associated with disease pathology, specifically round inclusions. These findings are the first to establish that peripherin splicing abnormalities occur in ALS, generating aggregation-prone splice isoforms.

Key words: peripherin; splice variant; isoform; ALS; intron retention; intermediate filament

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Received July 16, 2007; revised Nov. 30, 2007; accepted Dec. 29, 2007.

Correspondence should be addressed to Dr. Janice Robertson, Centre for Research in Neurodegenerative Diseases, University of Toronto, Tanz Building, 6 Queen's Park Crescent West, Toronto, Ontario, Canada M5S 3H2. Email: jan.robertson{at}utoronto.ca

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