Aberrant septin 11 is associated with sporadic frontotemporal lobar degeneration

Yair M. Gozal, Nicholas T. Seyfried, Marla Gearing, Jonathan D. Glass, Craig J. Heilman, Joanne Wuu, Duc M. Duong, Dongmei Cheng, Qiangwei Xia, Howard D. Rees, Jason J. Fritz, Deborah S. Cooper, Junmin Peng, Allan I. Levey, James J. Lah

Research output: Contribution to journalArticle

10 Scopus citations

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.

Original languageEnglish (US)
Article number82
JournalMolecular Neurodegeneration
Volume6
Issue number1
DOIs
StatePublished - Nov 30 2011
Externally publishedYes

Keywords

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

ASJC Scopus subject areas

  • Cellular and Molecular Neuroscience
  • Clinical Neurology
  • Molecular Biology

Fingerprint Dive into the research topics of 'Aberrant septin 11 is associated with sporadic frontotemporal lobar degeneration'. Together they form a unique fingerprint.

  • Cite this

    Gozal, Y. M., Seyfried, N. T., Gearing, M., Glass, J. D., Heilman, C. J., Wuu, J., Duong, D. M., Cheng, D., Xia, Q., Rees, H. D., Fritz, J. J., Cooper, D. S., Peng, J., Levey, A. I., & Lah, J. J. (2011). Aberrant septin 11 is associated with sporadic frontotemporal lobar degeneration. Molecular Neurodegeneration, 6(1), [82]. https://doi.org/10.1186/1750-1326-6-82