Research article
Aberrant septin 11 is associated with sporadic frontotemporal lobar degeneration
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* Corresponding author: James J Lah jlah@emory.edu
- † Equal contributors
1 Department of Neurology, Emory University School of Medicine, Atlanta, GA 30322. USA
2 Department of Human Genetics, Emory University School of Medicine, Atlanta, GA 30322. USA
3 Emory Proteomics Service Center, Emory University School of Medicine, Atlanta, GA 30322. USA
4 Center for Neurodegenerative Diseases, Alzheimer's Disease Research Center, Emory University School of Medicine, Atlanta, GA 30322. USA
Molecular Neurodegeneration 2011, 6:82 doi:10.1186/1750-1326-6-82
Published: 29 November 2011Abstract
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.