Defective neuritogenesis in Abcd1/2 deficient rat neurons due to intrinsic and astrocyte-dependent mechanisms

Abstract

X-linked adrenoleukodystrophy (X-ALD) is a rare neurometabolic and demyelinating disorder caused by loss of function mutations of the ABCD1 transporter that imports very-long-chain fatty acids (VLCFA) into the peroxisome for beta-oxidation. Impaired ABCD1 function results in VLCFA accumulation, which ultimately causes lethal forms of X-ALD in children (CCALD) and adults (CAMN). Because X-ALD is a genetic disorder, we looked for signs of altered neurodevelopmental pathways in the transcriptomes of brain cortical tissues free of pathology from patients that died of CALD or CAMN. Several categories related to brain development, axonal growth, synaptic signaling and synaptic compartments were significantly dysregulated in both CALD and CAMN, suggesting that congenital circuit abnormalities might be structural in brains of mutated ABCD1 carriers. We partially dissected the cellular origin of dysregulated pathways using rat neuronal and astrocytic cultures in which X-ALD was modeled by silencing of Abcd1 and Abcd2 by RNA interference. Abcd2 was silenced lest it compensated for Abcd1 loss. Abcd1/2 deficient neurons presented higher rates of death, reduced sizes and defective formation of spines, dendrites and axons. The aberrant neuron development was caused by cell-autonomous and astrocyte-dependent mechanisms, and involved Wnt signaling, as suggested by the rescue of the expression of a synaptic gene upon pharmacological activation of the Wnt pathway. As recently proposed for neurogenetic disorders such as Huntingtons disease, our data suggest that X-ALD has a neurodevelopmental component that may cause psychiatric alterations and prime neural circuits for neurodegeneration. If this is the case, therapies aimed at restoring neural-circuit function in neurodevelopmental disorders may be reprofiled for X-ALD therapeutics.