{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,5,8]],"date-time":"2026-05-08T00:35:38Z","timestamp":1778200538117,"version":"3.51.4"},"reference-count":47,"publisher":"Wiley","issue":"3","license":[{"start":{"date-parts":[[2023,12,26]],"date-time":"2023-12-26T00:00:00Z","timestamp":1703548800000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"funder":[{"DOI":"10.13039\/100012489","name":"Boston Area Diabetes Endocrinology Research Center","doi-asserted-by":"publisher","award":["DK057521"],"award-info":[{"award-number":["DK057521"]}],"id":[{"id":"10.13039\/100012489","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Annals of Neurology"],"published-print":{"date-parts":[[2024,3]]},"abstract":"<jats:sec><jats:title>Objective<\/jats:title><jats:p>X\u2010linked adrenoleukodystrophy is caused by mutations in the peroxisomal half\u2010transporter <jats:italic>ABCD1<\/jats:italic>. 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.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>Neuronal expression of ABCD1 during development was assessed in mice and humans. ABCD1\u2010deficient mice and human brain tissues were examined for corresponding pathology. Next, we silenced <jats:italic>ABCD1<\/jats:italic> in cholinergic Sh\u2010sy5y neurons to investigate its impact on neuronal function. Finally, we tested adeno\u2010associated virus vector\u2010mediated <jats:italic>ABCD1<\/jats:italic> delivery to the brain in mice with adrenomyeloneuropathy.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>ABCD1 is highly expressed in neurons located in the periaqueductal gray matter, basal forebrain and hypothalamus. In ABCD1\u2010deficient mice (<jats:italic>Abcd1<\/jats:italic>\u2212\/y), these structures showed mild accumulations of \u03b1\u2010synuclein. Similarly, healthy human controls had high expression of ABCD1 in deep gray nuclei, whereas X\u2010ALD 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 <jats:italic>ABCD1<\/jats:italic> in Sh\u2010sy5y neurons impaired expression of functional proteins and decreased acetylcholine levels, similar to observations in plasma of <jats:italic>Abcd1<\/jats:italic>\u2212\/y mice. Notably, hind limb clasping in <jats:italic>Abcd1<\/jats:italic>\u2212\/y mice was corrected through transduction of <jats:italic>ABCD1<\/jats:italic> in basal forebrain neurons following intracerebroventricular gene delivery.<\/jats:p><\/jats:sec><jats:sec><jats:title>Interpretation<\/jats:title><jats:p>Our study suggests that the basal forebrain\u2013cortical 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. 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