X-linked adrenoleukodystrophy (X-ALD) is a rare disease caused by mutations in the peroxisomal ABCD1 transporter, with two major clinical manifestations of neurodegeneration: acute and lethal brain demyelination in the child cerebral X-ALD (CCALD), and chronic degeneration of spinal-cord tracts and peripheral neuropathy in the adult adrenomyeloneuropathy (AMN). Psychiatric alterations are an early sign of CCALD and coexist with spinal-cord and peripheral neurodegeneration in AMN, revealing concomitant brain pathology. Since X-ALD is a genetic condition, we sought to determine whether psychiatric alterations could be due, at least in part, to abnormal formation of brain circuits during brain development and not to neurodegeneration. To this end, we used a top-down approach, moving from patient transcriptome data, where we searched for dysregulated neurodevelopmental pathways, to in vitro murine models of X-ALD based on Abcd1/Abcd2 silencing to dissect out astrocyte versus neurons compartmentalization. There are four major findings. First, developmental pathways are dysregulated in CCALD, CAMN and in ABCD-null neuronal cultures, associated with altered neuritogenesis, spinogenesis, and axonogenesis. Second, aberrant spine growth is in part due to alterations in canonical Wnt signalling alteration since the spinogenesis is partially rescued by activation of WNT pathways by pharmacological GSK-3 inhibition. Third, cholesterol synthesis and localization is changed in ABCD-null astrocytes. Four, silencing of ABCD transporters causes metabolic alterations in astrocytes including fatty acid oxidation impairment, increase of the ratio NAD+/NADH, ATP depletion, decreases in total glutathione, suggesting joint impairment of antioxidant defense and bioenergetics. Fifth, X-ALD astrocytes present altered agonist-induced calcium signaling and ER stress. We conclude that i) X-ALD has a neurodevelopmental component that may account for psychiatric symptoms, and perhaps contribute to the progression of CCALD, and to the conversion of AMN into a cerebral condition, and ii) metabolic and excitability dysregulation in astrocytes support global astrocytic dysfunction that may jeopardize computational and homeostatic role of astrocytes in neural circuits.
|Date of Award||28 Nov 2019|
|Supervisor||Maria Elena Galea Rodriguez Velasco (Director), Maria Elena Galea Rodriguez Velasco (Tutor) & Roser Masgrau Juanola (Director)|