ALS-associated peripherin spliced transcripts form distinct protein inclusions that are neuroprotective against oxidative stress

Intracellular proteinaceous inclusions are well-documented hallmarks of the fatal motor neuron disorder amyotrophic lateral sclerosis (ALS). The pathological significance of these inclusions remains unknown. Peripherin, a type III intermediate filament protein, is upregulated in ALS and identified a...

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Published in:	Experimental neurology Vol. 261; pp. 217 - 229
Main Authors:	McLean, Jesse R., Smith, Gaynor A., Rocha, Emily M., Osborn, Teresia M., Dib, Samar, Hayes, Melissa A., Beagan, Jonathan A., Brown, Tana B., Lawson, Tristan F.S., Hallett, Penelope J., Robertson, Janice, Isacson, Ole
Format:	Journal Article
Language:	English
Published:	United States Elsevier Inc 01-11-2014
Subjects:	Aggregation Amyotrophic lateral sclerosis (ALS) Carcinoma - pathology Cell Line, Tumor DNA-Binding Proteins - metabolism Dose-Response Relationship, Drug Humans Hydrogen Peroxide - pharmacology Inclusion Inclusion Bodies - genetics Inclusion Bodies - metabolism Intermediate filament Oxidative Stress - drug effects Oxidative Stress - genetics Peripherin Peripherins - genetics Peripherins - metabolism Protein Aggregation, Pathological - genetics Protein Isoforms - genetics Protein Isoforms - metabolism Proto-Oncogene Proteins c-myc - metabolism RNA, Messenger - metabolism Splicing Stress TDP-43 Time Factors Transfection Ubiquitin - metabolism Vimentin - metabolism Aggregation Inclusion Splicing Amyotrophic lateral sclerosis (ALS) TDP-43 Peripherin Intermediate filament Stress
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Summary:	Intracellular proteinaceous inclusions are well-documented hallmarks of the fatal motor neuron disorder amyotrophic lateral sclerosis (ALS). The pathological significance of these inclusions remains unknown. Peripherin, a type III intermediate filament protein, is upregulated in ALS and identified as a component within different types of ALS inclusions. The formation of these inclusions may be associated with abnormal peripherin splicing, whereby an increase in mRNA retaining introns 3 and 4 (Per-3,4) leads to the generation of an aggregation-prone isoform, Per-28. During the course of evaluating peripherin filament assembly in SW-13 cells, we identified that expression of both Per-3,4 and Per-28 transcripts formed inclusions with categorically distinct morphology: Per-3,4 was associated with cytoplasmic condensed/bundled filaments, small inclusions (<10μM), or large inclusions (≥10μM); while Per-28 was associated with punctate inclusions in the nucleus and/or cytoplasm. We found temporal and spatial changes in inclusion morphology between 12 and 48h post-transfected cells, which were accompanied by unique immunofluorescent and biochemical changes of other ALS-relevant proteins, including TDP-43 and ubiquitin. Despite mild cytotoxicity associated with peripherin transfection, Per-3,4 and Per-28 expression increased cell viability during H2O2-mediated oxidative stress in BE(2)-M17 neuroblastoma cells. Taken together, this study shows that ALS-associated peripherin isoforms form dynamic cytoplasmic and intranuclear inclusions, effect changes in local endogenous protein expression, and afford cytoprotection against oxidative stress. These findings may have important relevance to understanding the pathophysiological role of inclusions in ALS. •ALS-associated peripherin isoforms form distinct cytoplasmic or nuclear inclusions.•Peripherin inclusions change morphology and subcellular location over time.•Peripherin inclusions alter TDP-43, ubiquitin, and vimentin expression.•Per-3,4 and Per-28 expression protect neuroblastoma cells from oxidative stress.
Bibliography:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23
ISSN:	0014-4886 1090-2430
DOI:	10.1016/j.expneurol.2014.05.024