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VCP mutations causing frontotemporal lobar degeneration disrupt localization of TDP-43 and induce cell death.

ABSTRACT: Frontotemporal lobar degeneration (FTLD) with inclusion body myopathy and Paget disease of bone is a rare, autosomal dominant disorder caused by mutations in the VCP (valosin-containing protein) gene. The disease is characterized neuropathologically by frontal and temporal lobar atrophy, neuron loss and gliosis, and ubiquitin-positive inclusions (FTLD-U), which are distinct from those seen in other sporadic and familial FTLD-U entities. The major component of the ubiquitinated inclusions of FTLD with VCP mutation is TDP-43 (TAR DNA-binding protein of 43 kDa). TDP-43 proteinopathy links sporadic amyotrophic lateral sclerosis, sporadic FTLD-U, and most familial forms of FTLD-U. Understanding the relationship between individual gene defects and pathologic TDP-43 will facilitate the characterization of the mechanisms leading to neurodegeneration. Using cell culture models, we have investigated the role of mutant VCP in intracellular trafficking, proteasomal function, and cell death and demonstrate that mutations in the VCP gene 1) alter localization of TDP-43 between the nucleus and cytosol, 2) decrease proteasome activity, 3) induce endoplasmic reticulum stress, 4) increase markers of apoptosis, and 5) impair cell viability. These results suggest that VCP mutation-induced neurodegeneration is mediated by several mechanisms.

SUBMITTER: Gitcho MA

PROVIDER: S-EPMC2673306 | biostudies-literature | 2009 May

REPOSITORIES: biostudies-literature

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VCP mutations causing frontotemporal lobar degeneration disrupt localization of TDP-43 and induce cell death.

Gitcho Michael A MA Strider Jeffrey J Carter Deborah D Taylor-Reinwald Lisa L Forman Mark S MS Goate Alison M AM Cairns Nigel J NJ

The Journal of biological chemistry 20090223 18

Frontotemporal lobar degeneration (FTLD) with inclusion body myopathy and Paget disease of bone is a rare, autosomal dominant disorder caused by mutations in the VCP (valosin-containing protein) gene. The disease is characterized neuropathologically by frontal and temporal lobar atrophy, neuron loss and gliosis, and ubiquitin-positive inclusions (FTLD-U), which are distinct from those seen in other sporadic and familial FTLD-U entities. The major component of the ubiquitinated inclusions of FTLD ...[more]

PMID: 19237541

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Project description:ImportanceBiomarkers are lacking that can discriminate frontotemporal lobar degeneration (FTLD) associated with tau (FTLD-tau) or TDP-43 (FTLD-TDP).ObjectiveTo test whether plasma biomarkers glial fibrillary acidic protein (GFAP), neurofilament light chain (NfL), or their ratio (GFAP/NfL) differ between FTLD-tau and FTLD-TDP.Design, setting, and participantsThis retrospective cross-sectional study included data from 2009 to 2020 from the University of Pennsylvania Integrated Neurodegenerative Disease Database, with a median (IQR) follow-up duration of 2 (0.3-4.2) years. The training sample was composed of patients with autopsy-confirmed and familial FTLD; nonimpaired controls were included as a reference group. The independent validation sample included patients with FTD with a clinical diagnosis of progressive supranuclear palsy syndrome (PSPS) associated with tau (PSPS-tau) or amytrophic lateral sclerosis (ALS) associated with TDP-43 (ALS-TDP). In patients with FTLD with autopsy-confirmed or variant-confirmed pathology, receiver operating characteristic (ROC) curves tested the GFAP/NfL ratio and established a pathology-confirmed cut point. The cut point was validated in an independent sample of patients with clinical frontotemporal dementia (FTD). Data were analyzed from February to July 2022.ExposuresClinical, postmortem histopathological assessments, and plasma collection.Main outcomes and measuresROC and area under the ROC curve (AUC) with 90% CIs evaluated discrimination of pure FTLD-tau from pure FTLD-TDP using plasma GFAP/NfL ratio; the Youden index established optimal cut points. Sensitivity and specificity of cut points were assessed in an independent validation sample.ResultsOf 349 participants with available plasma data, 234 met inclusion criteria (31 controls, 141 in the training sample, and 62 in the validation sample). In the training sample, patients with FTLD-tau were older than patients with FTLD-TDP (FTLD-tau: n = 46; mean [SD] age, 65.8 [8.29] years; FTLD-TDP: n = 95; mean [SD] age, 62.3 [7.82] years; t84.6 = 2.45; mean difference, 3.57; 95% CI, 0.67-6.48; P = .02) but with similar sex distribution (FTLD-tau: 27 of 46 [59%] were male; FTLD-TDP: 51 of 95 [54%] were male; χ21 = 0.14; P = .70). In the validation sample, patients with PSPS-tau were older than those with ALS-TDP (PSPS-tau: n = 31; mean [SD] age, 69.3 [7.35] years; ALS-TDP: n = 31; mean [SD] age, 54.6 [10.17] years; t54.6 = 6.53; mean difference, 14.71; 95% CI, 10.19-19.23; P < .001) and had fewer patients who were male (PSPS-tau: 9 of 31 [29%] were male; ALS-TDP: 22 of 31 [71%] were male; χ21 = 9.3; P = .002). ROC revealed excellent discrimination of FTLD-tau from FTLD-TDP by plasma GFAP/NfL ratio (AUC = 0.89; 90% CI, 0.82-0.95; sensitivity = 0.73; 90% CI, 0.65-0.89; specificity = 0.89; 90% CI, 0.78-0.98), which was higher than either GFAP level alone (AUC = 0.65; 90% CI, 0.54-0.76) or NfL levels alone (AUC = 0.75; 90% CI, 0.64-0.85). In the validation sample, there was sensitivity of 0.84 (90% CI, 0.66-0.94) and specificity of 0.81 (90% CI, 0.62-0.91) when applying the autopsy-derived plasma GFAP/NfL threshold.Conclusions and relevanceThe plasma ratio of GFAP/NfL may discriminate FTLD-tau from FTLD-TDP.

Project description:TAR-DNA binding protein-43 (TDP-43) proteinopathy is seen in multiple brain diseases. A standardized terminology was recommended recently for common age-related TDP-43 proteinopathy: limbic-predominant, age-related TDP-43 encephalopathy (LATE) and the underlying neuropathological changes, LATE-NC. LATE-NC may be co-morbid with Alzheimer's disease neuropathological changes (ADNC). However, there currently are ill-defined diagnostic classification issues among LATE-NC, ADNC, and frontotemporal lobar degeneration with TDP-43 (FTLD-TDP). A practical challenge is that different autopsy cohorts are composed of disparate groups of research volunteers: hospital- and clinic-based cohorts are enriched for FTLD-TDP cases, whereas community-based cohorts have more LATE-NC cases. Neuropathological methods also differ across laboratories. Here, we combined both cases and neuropathologists' diagnoses from two research centres-University of Pennsylvania and University of Kentucky. The study was designed to compare neuropathological findings between FTLD-TDP and pathologically severe LATE-NC. First, cases were selected from the University of Pennsylvania with pathological diagnoses of either FTLD-TDP (n = 33) or severe LATE-NC (mostly stage 3) with co-morbid ADNC (n = 30). Sections from these University of Pennsylvania cases were cut from amygdala, anterior cingulate, superior/mid-temporal, and middle frontal gyrus. These sections were stained for phospho-TDP-43 immunohistochemically and evaluated independently by two University of Kentucky neuropathologists blinded to case data. A simple set of criteria hypothesized to differentiate FTLD-TDP from LATE-NC was generated based on density of TDP-43 immunoreactive neuronal cytoplasmic inclusions in the neocortical regions. Criteria-based sensitivity and specificity of differentiating severe LATE-NC from FTLD-TDP cases with blind evaluation was ∼90%. Another proposed neuropathological feature related to TDP-43 proteinopathy in aged individuals is 'Alpha' versus 'Beta' in amygdala. Alpha and Beta status was diagnosed by neuropathologists from both universities (n = 5 raters). There was poor inter-rater reliability of Alpha/Beta classification (mean κ = 0.31). We next tested a separate cohort of cases from University of Kentucky with either FTLD-TDP (n = 8) or with relatively 'pure' severe LATE-NC (lacking intermediate or severe ADNC; n = 14). The simple criteria were applied by neuropathologists blinded to the prior diagnoses at University of Pennsylvania. Again, the criteria for differentiating LATE-NC from FTLD-TDP was effective, with sensitivity and specificity ∼90%. If more representative cases from each cohort (including less severe TDP-43 proteinopathy) had been included, the overall accuracy for identifying LATE-NC was estimated at >98% for both cohorts. Also across both cohorts, cases with FTLD-TDP died younger than those with LATE-NC (P < 0.0001). We conclude that in most cases, severe LATE-NC and FTLD-TDP can be differentiated by applying simple neuropathological criteria.

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VCP mutations causing frontotemporal lobar degeneration disrupt localization of TDP-43 and induce cell death.

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VCP mutations causing frontotemporal lobar degeneration disrupt localization of TDP-43 and induce cell death.

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