Date of Presentation
5-4-2023 12:00 AM
College
School of Osteopathic Medicine
Poster Abstract
Canavan disease (CD) is an inherited leukodystrophy caused by inactivating mutations to the glial enzyme aspartoacylase (ASPA). ASPA catabolizes neuronal N-acetylaspartate (NAA) into free acetate and aspartate and loss of this function results in the chronic elevation of non-catabolized NAA and the failure of developmental myelination. Elevated NAA is thought to cause damage to myelin and myelin-producing cells (oligodendrocytes, but the viability of neurons in CD is relatively unexplored. We compare here the progressive degeneration of neurons in two regions of the CD mouse brain, the thalamus and the cortex, distinguished by differing degrees of vacuolation, and show that the relatively more affected thalamus is punctuated by significant neuron from 3 weeks of age onwards while cortical neurons appear relatively unaffected. Thalamic neuron loss is most acute at 3-6 weeks and mirrors parallel oligodendrocyte loss. Oligodendrocyte loss in the cortex during the same developmental window is comparable to the thalamus but is not associated with significant neuron loss. Both the thalamus and cortex present with elevated expression of Nat8L, the rate-limiting enzyme for NAA synthesis, but severe vacuolation is seen only in the thalamus, indicating the loss of glial ASPA is more directly linked to vacuolation than is elevated NAA alone.
Keywords
Canavan Disease, Hereditary Central Nervous System Demyelinating Diseases, Animal Disease Models, Thalamus, Nat8L
Disciplines
Congenital, Hereditary, and Neonatal Diseases and Abnormalities | Disease Modeling | Genetic Processes | Laboratory and Basic Science Research | Medical Neurobiology | Medicine and Health Sciences | Nervous System Diseases | Neurology
Document Type
Poster
Included in
Congenital, Hereditary, and Neonatal Diseases and Abnormalities Commons, Disease Modeling Commons, Genetic Processes Commons, Laboratory and Basic Science Research Commons, Medical Neurobiology Commons, Nervous System Diseases Commons, Neurology Commons
Differential Degeneration of Neurons in a Mouse Model of Canavan Disease
Canavan disease (CD) is an inherited leukodystrophy caused by inactivating mutations to the glial enzyme aspartoacylase (ASPA). ASPA catabolizes neuronal N-acetylaspartate (NAA) into free acetate and aspartate and loss of this function results in the chronic elevation of non-catabolized NAA and the failure of developmental myelination. Elevated NAA is thought to cause damage to myelin and myelin-producing cells (oligodendrocytes, but the viability of neurons in CD is relatively unexplored. We compare here the progressive degeneration of neurons in two regions of the CD mouse brain, the thalamus and the cortex, distinguished by differing degrees of vacuolation, and show that the relatively more affected thalamus is punctuated by significant neuron from 3 weeks of age onwards while cortical neurons appear relatively unaffected. Thalamic neuron loss is most acute at 3-6 weeks and mirrors parallel oligodendrocyte loss. Oligodendrocyte loss in the cortex during the same developmental window is comparable to the thalamus but is not associated with significant neuron loss. Both the thalamus and cortex present with elevated expression of Nat8L, the rate-limiting enzyme for NAA synthesis, but severe vacuolation is seen only in the thalamus, indicating the loss of glial ASPA is more directly linked to vacuolation than is elevated NAA alone.