Autophagy induction halts axonal degeneration in a mouse model of X-adrenoleukodystrophy

Abstract

X-linked adrenoleukodystrophy (X-ALD) is a rare neurometabolic disease characterized by the accumulation of very long chain fatty acids (VLCFAs) due to a loss of function of the peroxisomal transporter ABCD1. Here, using in vivo and in vitro models, we demonstrate that autophagic flux was impaired due to elevated mammalian target of rapamycin (mTOR) signaling, which contributed to X-ALD pathogenesis. We also show that excess VLCFAs downregulated autophagy in human fibroblasts. Furthermore, mTOR inhibition by a rapamycin derivative (temsirolimus) restored autophagic flux and inhibited the axonal degenerative process as well as the associated locomotor impairment in the Abcd1−/Abcd2−/− mouse model. This process was mediated through the restoration of proteasome function and redox as well as metabolic homeostasis. These findings provide the first evidence that links impaired autophagy to X-ALD, which may yield a therapy based on autophagy activators for adrenomyeloneuropathy patients.Electronic supplementary materialThe online version of this article (doi:10.1007/s00401-014-1378-8) contains supplementary material, which is available to authorized users.

Alterations of autophagy in the peripheral neuropathy Charcot-Marie-Tooth type 2B

“…52–56 Axons and dendrites are particularly sensitive to accumulation of protein aggregates or damaged organelles and a growing body of evidence indicates that altered (both increased or inhibited) autophagy can lead to axonal and/or dendrite degeneration. 57–60 In addition, autophagy is induced after axonal damage in order to halt axonal degeneration. 61 , 62 Therefore, the impaired ability of CMT2B-causing RAB7 mutant proteins to induce autophagy could limit this important neuroprotective mechanism and, in the long term, support the establishment of CMT2B disease.…”

Oxidative stress, mitochondrial and proteostasis malfunction in adrenoleukodystrophy: A paradigm for axonal degeneration

“…Taking advantage of the Abcd1 -mouse model, and keeping track of the data obtained with expression microarrays [53], we uncovered an early-onset oxidative damage, which may be a major contributor to disease pathogenesis in the mouse [33,49,55,58,59]. This is a common feature to neurodegenerative diseases and aging, and is found in X-ALD patients in brain tissue as well as in peripheral cells or fluids such as fibroblasts, erythrocytes, peripheral mononuclear cells and plasma [46,[58][59][60][61][62].…”

“…Lately, lipoic acid has been shown to rescue the hypometabolic state in a mouse model of AD, characterized by low levels of glutamine, glutamate, aspartate and N-acetylaspartate, metabolites of the TCA cycle [72]. We thus treated the X-ALD mice with the cocktail above mentioned, and obtained a neutralization of oxidative stress and lesions to proteins; preserved bioenergetic homeostasis maintaining ATP and NADH levels by recovering normal levels of oxidation on key proteins of Krebs cycle and glycolysis; halted signs of axonal degeneration in immunohistological stainings; and prevented locomotor impairment in bar-cross and treadmill tests [33][34][35][36].…”

“…Both Abcd1 -and Abcd1 -/Abcd2 -/-mice are bona fide models of mild, late-onset axonopathy exhibited by AMN patients. These models are instrumental in dissecting pathomechanisms of AMN [49][50][51][52][53] and importantly, in pinpointing and evaluating tailored therapies [30,[33][34][35][36]54].…”

“…Oral administration of "Lorenzo's oil" has been used, but its clinical efficacy and clinical indications have been controversial for more than 15 years [32]. Nonetheless, more recent successful pharmacological preclinical tests in the X-ALD mouse model warrant translation into the clinic [33][34][35][36].…”