Loss of AMPKα1 in neuroinflammatory phenotype of X-linked adrenoleukodystrophy (HUM2P.335)

Abstract

Abstract X-linked adrenoleukodystrophy (X-ALD) is the most common inherited neuroinflammatory demyelinating leukodystrophy. All X-ALD patients present with mutations in the ABCD1 gene, which encodes a peroxisomal adenosine triphosphate (ATP)-binding cassette transporter protein (ABCD1). X-ALD is a complex disease where the same mutation in the ALD gene (ABCD1) can lead to clinically very distinct phenotypes; a fatal neuroinflammatory childhood cerebral ALD (ALD) or the relatively benign disease of adrenomyeloneuropathy (AMN). Further, no relationship could be established between genotype and severity of the disease as same mutation is known to give different phenotypes, even within a family. We recently documented a role for decreased AMP kinaseα1 (AMPKα1) levels in initiating severe inflammatory and demyelinating phenotype in the CNS of AMPKα1-knockout mice. Abundant data is also available that implicates loss of AMPK in generating spontaneous inflammatory response in several cell types including immune cells. Our data using healthy control, AMN and ALD patient-derived skin fibroblasts and lymphocytes documents, for the first time, loss of a metabolic gene- AMPKα1 in ALD patient-derived fibroblasts and lymphocytes. Consistent with this, the basal expression of inflammatory cytokines (iNOS and IL-6) were increased in ALD patient-derived lymphocytes. Together these observations suggest that AMPKα1 may be involved in the progression of benign AMN to neuroinflammatory ALD phenotype.