Role of Basal Forebrain Neurons in Adrenomyeloneuropathy in Mice and Humans
Open accessAbstract
Objective: X‐linked adrenoleukodystrophy is caused by mutations in the peroxisomal half‐transporter ABCD1. The most common manifestation is adrenomyeloneuropathy, a hereditary spastic paraplegia of adulthood. The present study set out to understand the role of neuronal ABCD1 in mice and humans with adrenomyeloneuropathy. Methods: Neuronal expression of ABCD1 during development was assessed in mice and humans. ABCD1‐deficient mice and human brain tissues were examined for corresponding pathology. Next, we silenced ABCD1 in cholinergic Sh‐sy5y neurons to investigate its impact on neuronal function. Finally, we tested adeno‐associated virus vector‐mediated ABCD1 delivery to the brain in mice with adrenomyeloneuropathy. Results: ABCD1 is highly expressed in neurons located in the periaqueductal gray matter, basal forebrain and hypothalamus. In ABCD1‐deficient mice (Abcd1−/y), these structures showed mild accumulations of α‐synuclein. Similarly, healthy human controls had high expression of ABCD1 in deep gray nuclei, whereas X‐ALD patients showed increased levels of phosphorylated tau, gliosis, and complement activation in those same regions, albeit not to the degree seen in neurodegenerative tauopathies. Silencing ABCD1 in Sh‐sy5y neurons impaired expression of functional proteins and decreased acetylcholine levels, similar to observations in plasma of Abcd1−/y mice. Notably, hind limb clasping in Abcd1−/y mice was corrected through transduction of ABCD1 in basal forebrain neurons following intracerebroventricular gene delivery. Interpretation: Our study suggests that the basal forebrain–cortical cholinergic pathway may contribute to dysfunction in adrenomyeloneuropathy. Rescuing peroxisomal transport activity in basal forebrain neurons and supporting glial cells might represent a viable therapeutic strategy. ANN NEUROL 2024;95:442–458
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Electron microscopy reveals characteristic cytoplasmic inclusions (spicules) in oligodendrocytes, perivascular macrophages, and/or microglia but not in astrocytes.
“Electron microscopy reveals characteristic cytoplasmic inclusions (“spicules”) in OLs, perivascular macrophages, and/or microglia but not in astrocytes.”
From Revisiting the Pathogenesis of X-Linked Adrenoleukodystrophy (2025) · cites this paper as [79]
VLCFA accumulation was decreased by 9-24% in the spinal cord white matter after neuron-targeting gene therapy.
“VLCFA accumulation was decreased by 9–24% in the spinal cord white matter [79,290,306].”
From Revisiting the Pathogenesis of X-Linked Adrenoleukodystrophy (2025) · cites this paper as [79]
Intracerebroventricular injection of the same vector induced hABCD1 expression in spinal cord neurons, astrocytes, and microglia, but not in OLs.
“Intracerebroventricular injection of the same vector induced hABCD1 expression in spinal cord neurons, astrocytes, and microglia, but not in OLs [79,291].”
From Revisiting the Pathogenesis of X-Linked Adrenoleukodystrophy (2025) · cites this paper as [79]
The co-transduction of astrocytes may have played an additional role in the gene therapy effect.
“The co-transduction of astrocytes may have played an additional role, as suggested by previous gene therapy attempts that used a vector targeting neurons and astrocytes, but this had a more limited effect than the OL-targeting vector [79,290,291].”
From Revisiting the Pathogenesis of X-Linked Adrenoleukodystrophy (2025) · cites this paper as [79]
Restoration of ABCD1 expression of the neuron populations targeted in these studies had no significant or consistent effect on motor performance.
“In summary, restoration of ABCD1 expression of the neuron populations targeted in these studies had no significant or consistent effect on motor performance.”
From Revisiting the Pathogenesis of X-Linked Adrenoleukodystrophy (2025) · cites this paper as [79]
The cited routes of administration did not allow the vector to transduce neurons of the motor cortex from which corticospinal axons originate.
“In addition, the cited routes of administration did not allow the vector to transduce neurons of the motor cortex from which corticospinal axons originate.”
From Revisiting the Pathogenesis of X-Linked Adrenoleukodystrophy (2025) · cites this paper as [79]
Interpretation of neuron-targeting gene therapy results is hampered by the short-term design of these studies and by the fact that motor test performances were unexpectedly found comparable in 20-month-old untreated Abcd1−/− and wild type mice.
“The interpretation of these results is also hampered by the short-term design of these studies, and by the fact that motor test performances were unexpectedly found comparable in 20-month-old untreated Abcd1−/− and wild type mice [79].”
From Revisiting the Pathogenesis of X-Linked Adrenoleukodystrophy (2025) · cites this paper as [79]
An AAV9-CBA-hABCD1 vector targeting neurons and/or astrocytes had only a partial effect on disease phenotypes, notably motor deficits.
“It was previously observed that an AAV9-CBA-hABCD1 vector targeting neurons and/or astrocytes had only a partial effect on disease phenotypes, notably the motor deficits [79,290,291].”
From Revisiting the Pathogenesis of X-Linked Adrenoleukodystrophy (2025) · cites this paper as [79]
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“35 These fi ndings suggest that basal ganglia outputs in fl uence the generation and modulation of movement.”
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“15”
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Gene therapy for the leukodystrophies: From preclinical animal studies to clinical trials.
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Self-citation
- Authors
- Gong, Y., Laheji, F., Berenson, A., Li, Y., Moser, A., Qian, A., Frosch, M., Sadjadi, R., Hahn, R., Maguire, C. A., & Eichler, F.
- Affiliations
- Harvard University (US)
- Peroxisome Disease Lab Hugo W Moser Research Institute Baltimore MD USA
- Corresponding author
- Eichler, Florian
- ORCID
- Venue
- Annals of Neurology
- Publisher
- Wiley
- Published
- 2023-12-26
- Volume
- 95
- Issue
- 3
- Pages
- 442-458
- ISSN
- 0364-5134 (ISSN-L)
- 1531-8249
- PMC
- PMC10949091
- OpenAlex
- W4389484970
- Cited by
- 11
- References
- 12
- Citations by year
- 2026: 2 · 2025: 3 · 2024: 6
- FWCI
- 2.15
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Annals of Neurology (publishedVersion, cc-by-nc-nd)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- Boston Area Diabetes Endocrinology Research Center (DK057521)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Clinical Biochemistry › Metabolism and Genetic Disorders
- Health Sciences › Medicine › Physiology › Lysosomal Storage Disorders Research
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Hereditary Neurological Disorders
- Keywords
- adrenomyeloneuropathy, X-linked adrenoleukodystrophy, ABCD1, basal forebrain neurons, cholinergic neurons, SH-SY5Y cells, periaqueductal gray, hypothalamus, alpha-synuclein, tau phosphorylation, gliosis, complement activation, acetylcholine, AAV gene delivery, hereditary spastic paraplegia
- MeSH terms
- ATP Binding Cassette Transporter, Subfamily D, Member 1, Adrenoleukodystrophy, Adult, Animals, Humans, Neuroblastoma, Neurons, ATP-Binding Cassette Transporters, Cholinergic Agents, Mice, Basal Forebrain
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