Role of Basal Forebrain Neurons in Adrenomyeloneuropathy in Mice and Humans.

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 [ABSTRACT FROM AUTHOR]