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Author Notes:

Correspondence: jlah@emory.edu

YMG, JP, AIL, and JJL conceived and designed the overall study with help from NTS (proteomics), QX (proteomics), MG (pathology), JDG (pathology), JW (pathology), JJF (DNA constructs), and CJH (immunoassays).

YMG, NTS, DMD, DC, QX, and JP performed the proteomics studies.

YMG, MG, JDG, HDR, JJF, DSC, AIL, and JJL performed the IHC and immunoblotting experiments.

YMG, CJH, AIL, and JJL designed, developed, and characterized the SEPT11-specific antibody.

JW carried out statistical analyses in immunohistochemical studies.

YMG drafted the manuscript with help from all co-authors.

JP, AIL, and JJL coordinated the study and finalized the manuscript.

All authors read and approved the final manuscript.

The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

The authors declare that they have no competing interests.

Subjects:

Research Funding:

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:

  • Neurodegeneration
  • dementia
  • proteomics
  • mass spectrometry
  • ubiquitin
  • aggregates

Aberrant septin 11 is associated with sporadic frontotemporal lobar degeneration

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Journal Title:

Molecular Neurodegeneration

Volume:

Volume 6

Publisher:

, Pages 82-82

Type of Work:

Article | Final Publisher PDF

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.

Copyright information:

©2011 Gozal et al; licensee BioMed Central Ltd.

This is an Open Access work distributed under the terms of the Creative Commons Attribution 2.0 Generic License (http://creativecommons.org/licenses/by/2.0/).

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