{"database":"biostudies-literature","file_versions":[],"scores":null,"additional":{"submitter":["Gong Y"],"funding":["Boston Area Diabetes Endocrinology Research Center","NIDDK NIH HHS","NINDS NIH HHS","NIH HHS"],"pagination":["442-458"],"full_dataset_link":["https://www.ebi.ac.uk/biostudies/studies/S-EPMC10949091"],"repository":["biostudies-literature"],"omics_type":["Unknown"],"volume":["95(3)"],"pubmed_abstract":["<h4>Objective</h4>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.<h4>Methods</h4>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.<h4>Results</h4>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.<h4>Interpretation</h4>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."],"journal":["Annals of neurology"],"pubmed_title":["Role of Basal Forebrain Neurons in Adrenomyeloneuropathy in Mice and Humans."],"pmcid":["PMC10949091"],"funding_grant_id":["P30 DK135043","DK057521","P30 DK057521","P30 DK043351","U54 NS115052","S10 OD021577"],"pubmed_authors":["Li Y","Moser A","Berenson A","Hahn R","Frosch M","Laheji F","Eichler F","Qian A","Sadjadi R","Maguire CA","Gong Y"],"additional_accession":[]},"is_claimable":false,"name":"Role of Basal Forebrain Neurons in Adrenomyeloneuropathy in Mice and Humans.","description":"<h4>Objective</h4>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.<h4>Methods</h4>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.<h4>Results</h4>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.<h4>Interpretation</h4>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.","dates":{"release":"2024-01-01T00:00:00Z","publication":"2024 Mar","modification":"2025-04-04T19:27:23.378Z","creation":"2025-04-04T19:27:23.378Z"},"accession":"S-EPMC10949091","cross_references":{"pubmed":["38062617"],"doi":["10.1002/ana.26849"]}}