Aberrant septin 11 is associated with sporadic frontotemporal lobar degeneration

• Type of Material: Article
• Authors: Yair M Gozal, Emory University; Nicholas Seyfried, Emory University; Marla Gearing, Emory University; Jonathan D Glass, Emory University; Craig Heilman, Emory University; Joanne Wuu, Emory University; Duc Duong, Emory University; Dongmei Cheng, Emory University; Qiangwei Xia, Emory University; Howard D Rees III, Emory University; Jason J Fritz, Emory University; Deborah S Cooper, Emory University; Junmin Peng, Emory University; Allan I Levey, Emory University; James J Lah, Emory University
• Language: English
• Date: 2011-11-29
• Publisher: BioMed Central
• Publication Version: Final Published Version
• Copyright Statement: ©2011 Gozal et al; licensee BioMed Central Ltd.
• License: Creative Commons Attribution 2.0 Generic
• Final Published Version (URL): http://www.molecularneurodegeneration.com/content/6/1/82
• Title of Journal or Parent Work: Molecular Neurodegeneration
• Volume: 6
• Start Page: 82
• End Page: 82
• Grant/Funding Information: This work was supported by NIH grants P50 AG025688, P30 NS055077, Consortium for Frontotemporal Dementia Research (CFR), and NIH training grants F30 NS057902 to YMG and F32 NS007480 to NTS.
• Keywords: dementia; aggregates; Neurodegeneration; mass spectrometry; ubiquitin; proteomics
• Research Categories: Chemistry, Biochemistry; Biology, Neuroscience; Health Sciences, Pathology

Abstract

Background Detergent-insoluble protein accumulation and aggregation in the brain is one of the pathological hallmarks of neurodegenerative diseases. Here, we describe the identification of septin 11 (SEPT11), an enriched component of detergent-resistant fractions in frontotemporal lobar degeneration with ubiquitin-immunoreactive inclusions (FTLD-U), using large-scale unbiased proteomics approaches. Results We developed and applied orthogonal quantitative proteomic strategies for the unbiased identification of disease-associated proteins in FTLD-U. Using these approaches, we proteomically profiled detergent-insoluble protein extracts prepared from frontal cortex of FTLD-U cases, unaffected controls, or neurologic controls (i.e. Alzheimer's disease; AD). Among the proteins altered specifically in FTLD-U, we identified TAR DNA binding protein-43 (TDP-43), a known component of ubiquitinated inclusions. Moreover, we identified additional proteins enriched in detergent-resistant fractions in FTLD-U, and characterized one of them, SEPT11, in detail. Using independent highly sensitive targeted proteomics approaches, we confirmed the enrichment of SEPT11 in FTLD-U extracts. We further showed that SEPT11 is proteolytically cleaved into N-terminal fragments and, in addition to its prominent glial localization in normal brain, accumulates in thread-like pathology in affected cortex of FTLD-U patients. Conclusions The proteomic discovery of insoluble SEPT11 accumulation in FTLD-U, along with novel pathological associations, highlights a role for this cytoskeleton-associated protein in the pathogenesis of this complex disorder.