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Antioxidants halt axonal degeneration in a mouse model of X-adrenoleukodystrophy
Jone López-Erauskin1, Stéphane Fourcade, Jorge Galino
1Neurometabolic Diseases Laboratory, The Bellvitge Institute of Biomedical Research, Hospitalet de Liobregat, Barcelona, Spain.
Objective:
Axonal degeneration is a main contributor to disability in progressive neurodegenerative diseases in which oxidative stress is often identified as a pathogenic factor. We aim to demonstrate that antioxidants are able to improve axonal degeneration and locomotor deficits in a mouse model of X-adrenoleukodystrophy (X-ALD).
Methods:
X-ALD is a lethal disease caused by loss of function of the ABCD1 peroxisomal transporter of very long chain fatty acids (VLCFA). The mouse model for X-ALD exhibits a late onset neurological phenotype with locomotor disability and axonal degeneration in spinal cord resembling the most common phenotype of the disease, adrenomyeloneuropathy (X-AMN). Recently, we identified oxidative damage as an early event in life, and the excess of VLCFA as a generator of radical oxygen species (ROS) and oxidative damage to proteins in X-ALD.
Results:
Here, we prove the capability of the antioxidants N-acetyl-cysteine, α-lipoic acid, and α-tocopherol to scavenge VLCFA-dependent ROS generation in vitro. Furthermore, in a preclinical setting, the cocktail of the 3 compounds reversed: (1) oxidative stress and lesions to proteins, (2) immunohistological signs of axonal degeneration, and (3) locomotor impairment in bar cross and treadmill tests.
Interpretation:
We have established a direct link between oxidative stress and axonal damage in a mouse model of neurodegenerative disease. This conceptual proof of oxidative stress as a major disease-driving factor in X-AMN warrants translation into clinical trials for X-AMN, and invites assessment of antioxidant strategies in axonopathies in which oxidative damage might be a contributing factor.
Insights
Antioxidants successfully treated axonal degeneration and improved motor function in a mouse model of X-adrenoleukodystrophy (X-ALD). This study links oxidative stress to axonal damage, supporting antioxidant therapy for X-ALD and other neurodegenerative diseases.
Area of Science:
- Neuroscience
- Biochemistry
- Genetics
Background:
- X-linked Adrenoleukodystrophy (X-ALD) is a fatal neurodegenerative disease caused by ABCD1 transporter dysfunction.
- Oxidative stress, driven by excess very long-chain fatty acids (VLCFAs), is an early pathogenic event in X-ALD.
- Axonal degeneration and locomotor deficits are key features of X-ALD, particularly the adrenomyeloneuropathy (X-AMN) phenotype.
Purpose of the Study:
- To investigate the therapeutic potential of antioxidants in a mouse model of X-ALD.
- To establish a direct link between oxidative stress and axonal degeneration in X-ALD.
- To evaluate the efficacy of a combination antioxidant therapy in improving neurological deficits.
Main Methods:
- Utilized a mouse model of X-ALD exhibiting axonal degeneration and locomotor impairment.
- Investigated the in vitro capacity of N-acetyl-cysteine, α-lipoic acid, and α-tocopherol to scavenge VLCFA-dependent reactive oxygen species (ROS).
- Administered a cocktail of these three antioxidants in a preclinical setting to assess effects on oxidative stress, axonal damage, and motor function.
Main Results:
- Antioxidants effectively scavenged VLCFA-induced ROS in vitro.
- The antioxidant cocktail significantly reduced oxidative stress and protein damage in the X-ALD mouse model.
- Histological analysis revealed decreased axonal degeneration, and behavioral tests showed improved locomotor function.
Conclusions:
- Established a direct causal link between oxidative stress and axonal damage in X-ALD.
- Demonstrated that antioxidant therapy can reverse key pathological and functional deficits in a preclinical X-ALD model.
- Results support clinical trials for antioxidant strategies in X-AMN and other oxidative stress-related axonopathies.
