Dataset Information

X-linked Dystonia-Parkinsonism patient cells exhibit altered signaling via nuclear factor-kappa B.

ABSTRACT: X-linked Dystonia-Parkinsonism (XDP) is a progressive neurodegenerative disease involving the loss of medium spiny neurons within the striatum. An XDP-specific haplotype has been identified, consisting of seven sequence variants which cluster around the human TAF1 gene, but a direct relationship between any of these variants and disease pathogenesis has not yet been demonstrated. Because the pathogenic gene lesion remains unclear, it has been difficult to predict cellular pathways which are affected in XDP cells. To address that issue, we assayed expression of defined gene sets in XDP vs. control fibroblasts to identify networks of functionally-related transcripts which may be dysregulated in XDP patient cells. That analysis derived a 51-gene signature distinguishing XDP vs. control fibroblasts which mapped strongly to nuclear factor-kappa B (NF?B), a transcription factor pathway also implicated in the pathogenesis of other neurodegenerative diseases, including Parkinson's (PD) and Huntington's disease (HD). Constitutive and TNF?-evoked NF?B signaling was further evaluated in XDP vs. control fibroblasts based on luciferase reporter activity, DNA binding of NF?B subunits, and endogenous target gene transcription. Compared to control cells, XDP fibroblasts exhibited decreased basal NF?B activity and decreased levels of the active NF?B p50 subunit, but increased target gene expression in response to TNF?. NF?B signaling was further examined in neural stem cells differentiated from XDP and control induced pluripotent stem cell (iPSC) lines, revealing a similar pattern of increased TNF? responses in the patient lines compared to controls. These data indicate that an NF?B signaling phenotype is present in both patient fibroblasts and neural stem cells, suggesting this pathway as a site of dysfunction in XDP.

SUBMITTER: Vaine CA

PROVIDER: S-EPMC5316362 | biostudies-literature | 2017 Apr

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

X-linked Dystonia-Parkinsonism patient cells exhibit altered signaling via nuclear factor-kappa B.

Vaine Christine A CA Shin David D Liu Christina C Hendriks William T WT Dhakal Jyotsna J Shin Kyle K Sharma Nutan N Bragg D Cristopher DC

Neurobiology of disease 20161222

X-linked Dystonia-Parkinsonism (XDP) is a progressive neurodegenerative disease involving the loss of medium spiny neurons within the striatum. An XDP-specific haplotype has been identified, consisting of seven sequence variants which cluster around the human TAF1 gene, but a direct relationship between any of these variants and disease pathogenesis has not yet been demonstrated. Because the pathogenic gene lesion remains unclear, it has been difficult to predict cellular pathways which are affe ...[more]

PMID: 28017799

Similar Datasets

Project description:ImportanceAnecdotal evidence suggests that deep brain stimulation (DBS) of the internal globus pallidus (GPi) is effective in ameliorating dystonia in X-linked dystonia parkinsonism (XDP), a disease that is usually refractive to medical therapy.ObjectiveTo determine the efficacy of GPi-DBS in a cohort of patients with XDP in a prospective study and identify predictors of postoperative outcomes.Design, setting, and participantsThis observational prospective cohort study enrolled patients in February 2013 and was completed in December 2014. The patients were followed up for up to 46 months. Patients from the Philippines were treated in a single center in Lübeck, Germany and followed up in the Philippines. Sixteen men with XDP (mean [SD] age, 40.9 [7.3] years; disease duration, 1-6 years) from the Philippines with predominant dystonia were selected.ExposuresAll patients underwent bilateral GPi-DBS in Lübeck, Germany.Main outcomes and measuresClinical assessment included the motor parts of the Burke-Fahn-Marsden scale (BFMDRS-M) and the Unified Parkinson's Disease Rating Scale (UPDRS-III). T1-based basal ganglia volumetry was performed and correlated with postoperative outcomes.ResultsThe study participants included 16 Filipino men (mean age, 40.9 years). Masked video ratings revealed significant improvements of dystonia severity 1 week (-55%; range, -94% to 59%; P < .01) and 6 months (-59%; range, -100% to 22%; P < .001) after surgery. The UDPRS-III score also improved, albeit to a lesser extent (-19%; range, -54% to 95%; and -27%; range, -70% to 124%; respectively). Unmasked long-term follow-up confirmed the continued efficacy of GPi-DBS up to 46 months after surgery. Important secondary end points improved, including activities of daily living, pain severity, weight, and quality of life. Caudate atrophy was a predictor of a less beneficial outcome (r = 0.817, P = .004).Conclusions and relevanceInternal globus pallidus DBS had a positive association in XDP with predominant dystonia (the primary end point) and contributed to an improved quality of life (the secondary end point). The response to DBS occurred within 1 week. Given the inverse correlation of postoperative benefit and caudate atrophy, GPi-DBS should be considered early during the disease course. Close international collaboration, training, and funding from multiple sources enabled the sustainable follow-up of patients with XDP in the Philippines.

Dataset Information

X-linked Dystonia-Parkinsonism patient cells exhibit altered signaling via nuclear factor-kappa B.

Publications

X-linked Dystonia-Parkinsonism patient cells exhibit altered signaling via nuclear factor-kappa B.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets