Tauroursodeoxycholic bile acid arrests axonal degeneration by inhibiting the unfolded protein response in X-linked adrenoleukodystrophy

AbstractThe activation of the highly conserved unfolded protein response (UPR) is prominent in the pathogenesis of the most prevalent neurodegenerative disorders, such as Alzheimer ’s disease (AD), Parkinson’s disease (PD) and amyotrophic lateral sclerosis (ALS), which are classically characterized by an accumulation of aggregated or misfolded proteins. This activation is orchestrated by three endoplasmic reticulum (ER) stress sensors: PERK, ATF6 and IRE1. These sensors tr ansduce signals that induce the expression of the UPR gene programme. Here, we first identified an early activator of the UPR and investigated the role of a chronically activated UPR in the pathogenesis of X-linked adrenoleukodystrophy (X-ALD), a neurometabolic disorder that is caused by ABCD1 malfu nction; ABCD1 transports very long-chain fatty acids (VLCFA) into peroxisomes. The disease manifests as inflammatory demyelination in the brain or and/or degeneration of corticospinal tracts, thereby resulting in spastic paraplegia, with the accumulation of intracellular VLCFA instead of protein agg regates. Using X-ALD mouse model (Abcd1− andAbcd1−/Abcd2−/− mice) and X-ALD patient ’s fibroblasts and brain samples, we discovered an early engagement of the UPR. The response was characterized by the activation of the PERK and ATF6 pathways, but not the IRE1 pathway, showing a difference from the models of AD, PD or ALS. Inhibition of PERK leads to the disruption of homeostasis and increased apoptosis...
Source: Acta Neuropathologica - Category: Neurology Source Type: research