کد مقاله کد نشریه سال انتشار مقاله انگلیسی نسخه تمام متن
10755895 1050378 2014 6 صفحه PDF دانلود رایگان
عنوان انگلیسی مقاله ISI
Loss of AMP-activated protein kinase in X-linked adrenoleukodystrophy patient-derived fibroblasts and lymphocytes
موضوعات مرتبط
علوم زیستی و بیوفناوری بیوشیمی، ژنتیک و زیست شناسی مولکولی زیست شیمی
پیش نمایش صفحه اول مقاله
Loss of AMP-activated protein kinase in X-linked adrenoleukodystrophy patient-derived fibroblasts and lymphocytes
چکیده انگلیسی
X-Adrenoleukodystrophy (X-ALD) is a peroxisomal disorder characterized by accumulation of very-long-chain (VLC) fatty acids, which induces inflammatory disease and alterations in cellular redox, both of which are reported to play a role in the pathogenesis of the severe form of the disease (childhood cerebral ALD). While the mutation defect in ABCD1 gene is common to all forms of X-ALD it fails to account for the spectrum of phenotypic variability seen in X-ALD patients, strongly suggesting a role for as yet unidentified modifier gene(s). Here we report, for the first time, loss of AMP-activated protein kinase alpha1 (AMPKα1) in patient-derived fibroblasts and lymphocytes of the severe cerebral form of X-ALD (ALD), and not in the milder adrenomyeloneuropathy (AMN) form. Decrease in AMPK was observed at both protein and mRNA levels. AMPK loss in ALD patient-derived fibroblasts was associated with increased ubiquitination. Using the Seahorse Bioscience XFe96 Flux Analyzer for measuring the mitochondrial oxygen consumption and extracellular acidification rate we show that ALD patient-derived fibroblasts have a significantly lower “metabolic state” than AMN fibroblasts. Unstimulated ALD patient-derived lymphocytes had significantly higher proinflammatory gene expression. Selective AMPK loss represents a novel physiopathogenic factor in X-ALD disease mechanism. Strategies aimed at upregulating/recovering AMPK levels might have beneficial therapeutic effects in X-ALD.
ناشر
Database: Elsevier - ScienceDirect (ساینس دایرکت)
Journal: Biochemical and Biophysical Research Communications - Volume 445, Issue 1, 28 February 2014, Pages 126-131
نویسندگان
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