Aberrant regulation of the GSK-3β/NRF2 axis unveils a novel therapy for adrenoleukodystrophy

Area of Science:

• Neuroscience
• Metabolic Disorders
• Cellular Biology

Background:

• X-linked adrenoleukodystrophy (X-ALD) is a rare neurometabolic disease caused by ABCD1 dysfunction, leading to very long-chain fatty acid accumulation and oxidative stress.
• Oxidative damage and mitochondrial dysfunction are early hallmarks of X-ALD in patients and mouse models.

Purpose of the Study:

• To investigate the role of the nuclear factor erythroid 2-like 2 (NRF2) pathway in X-ALD.
• To explore the therapeutic potential of NRF2 activation in X-ALD models.

Main Methods:

• Utilized patient fibroblasts and Abcd1 knockout mouse models.
• Assessed NRF2 response, mitochondrial function, oxidative damage, and inflammation.
• Administered dimethyl fumarate (DMF), an NRF2 activator, to mouse models.

Main Results:

• Identified an impaired NRF2 response in X-ALD linked to aberrant GSK-3β activity.
• GSK-3β inhibitors reactivated NRF2 in patient fibroblasts.
• DMF treatment in mouse models normalized mitochondrial depletion, bioenergetic failure, oxidative damage, and inflammation.
• DMF halted axonal degeneration and locomotor deficits in mice.

Conclusions:

• Dysfunctional GSK-3β/NRF2 axis contributes to X-ALD pathogenesis.
• NRF2 activation, particularly with DMF, demonstrates significant therapeutic potential for X-ALD.
• Targeting the NRF2 pathway offers a promising strategy for treating X-ALD and other axonopathies.