Annals of neurology · 2023
Role of Basal Forebrain Neurons in Adrenomyeloneuropathy in Mice and Humans.
СтатьяПоддержка NIH: внешняя программаНазвание и аннотация: Перевод в очереди
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Gong Yi, Laheji Fiza, Berenson Anna, Li Yedda, Moser Ann, Qian April, Frosch Matthew, Sadjadi Reza, Hahn Ryan, Maguire Casey A, Eichler Florian
Аннотация
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.
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.