{"doi":"10.1002/ana.26849","title":"Role of Basal Forebrain Neurons in Adrenomyeloneuropathy in Mice and Humans","abstract":"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.","journal":"Annals of Neurology","year":2023,"id":348853,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":11,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9271,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2023-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":1092088,"name":"Fiza Laheji","orcid":null,"position":1,"is_corresponding":false},{"id":630298,"name":"Anna Berenson","orcid":"0000-0002-3782-6186","position":2,"is_corresponding":false},{"id":353507,"name":"Yedda Li","orcid":"0000-0001-7629-2757","position":3,"is_corresponding":false},{"id":254724,"name":"Ann B. Moser","orcid":"0000-0002-9147-1902","position":4,"is_corresponding":false},{"id":1092089,"name":"April Qian","orcid":null,"position":5,"is_corresponding":false},{"id":28993,"name":"Matthew P. Frosch","orcid":"0000-0002-3940-9861","position":6,"is_corresponding":false},{"id":288174,"name":"Reza Sadjadi","orcid":"0000-0003-3829-6030","position":7,"is_corresponding":false},{"id":1091580,"name":"Ryan Hahn","orcid":"0000-0003-3482-8247","position":8,"is_corresponding":false},{"id":271598,"name":"Casey A. Maguire","orcid":"0000-0001-8681-5179","position":9,"is_corresponding":false},{"id":298504,"name":"Florian Eichler","orcid":"0000-0001-6836-1089","position":10,"is_corresponding":false},{"id":1040132,"name":"Yi Gong","orcid":"0000-0002-2348-9772","position":0,"is_corresponding":true}],"reference_count":48,"raw_metadata":null,"created_at":"2026-07-19T01:12:10.335697Z","pmid":"38062617","pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}