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Abstract
BackgroundDetergent-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.ResultsWe 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.ConclusionsThe 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.
Highlights
Detergent-insoluble protein accumulation and aggregation in the brain is one of the pathological hallmarks of neurodegenerative diseases
TAR DNA binding protein-43 (TDP-43) is localized in the intracytoplasmic ubiquitinated inclusions of sporadic amyotrophic lateral sclerosis (ALS), a motor neuron disease often associated with frontotemporal lobar degeneration with ubiquitin-immunoreactive inclusions (FTLD-U) [3,6], and mutations in TDP-43 have been linked to ALS [7,8,9,10]
Discovery of altered proteins in Frontotemporal lobar degeneration (FTLD)-U by LC-MS/MS To identify differentially expressed proteins in FTLD-U, which like TDP-43 are enriched in detergent-insoluble brain fractions, we examined post-mortem samples using two independent shotgun quantitative proteomic approaches (Figure 1a-b)
Summary
Detergent-insoluble protein accumulation and aggregation in the brain is one of the pathological hallmarks of neurodegenerative diseases. FTLD is heterogeneous, and may present as a tauopathy, or more commonly, with tau-negative, ubiquitin-immunoreactive neurites and inclusions [2]. In 2006, mutations in the progranulin gene (GRN) were identified as the cause of chromosome 17linked FTLD-U [4,5]. This discovery was followed by the identification of TAR DNA-binding protein 43 (TDP43), the first major non-ubiquitin protein component of pathological inclusions in familial and sporadic FTLD-U [6]. TDP-43 is localized in the intracytoplasmic ubiquitinated inclusions of sporadic amyotrophic lateral sclerosis (ALS), a motor neuron disease often associated with FTLD-U [3,6], and mutations in TDP-43 have been linked to ALS [7,8,9,10]
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