UC Davis

Demyelinating disorders, including multiple sclerosis and Canavan disease, afflict millions worldwide, yet their underlying mechanisms remain largely elusive. Our study on Canavan disease utilized single-cell spatial-temporal transcriptomics and mass spectrometry imaging. This approach enabled us to profile 37,083 genes at 500 nm resolution and 85 lipids at 10 μm resolution, offering detailed insights into the dysregulated genes and metabolites affecting signal transduction, osmotic homeostasis, vision, auditory function, and circadian rhythm. The Canavan brain lacks aspartoacylase; therefore, N-acetylaspartate (NAA) cannot be utilized to generate acetyl-CoA, an essential precursor for lipid synthesis. Our data demonstrate that the alternate route for acetyl-CoA production, mediated by ATP:citrate lyase in citrate cleavage, is also impaired, thus contributing to the deficit in myelin lipid synthesis. Additionally, this impairment results in a broad attenuation of gene expression due to histone hypoacetylation and disturbances in the tricarboxylic acid (TCA) cycle. Such disruptions could manifest as increased oxidative stress, widespread reduction in protein synthesis, and decreased ATP production. Notably, our research also revealed that oligodendrocytes are more abundant but less communicative with neurons in Canavan disease. To restore their function at an early stage, we delivered adeno-associated viruses (AAVs) intracerebroventricularly to fetal mice. These AAVs were engineered to express the ASPA gene in oligodendrocytes, significantly alleviating disease symptoms. Additionally, we introduced two new methods, BrainSegmenter and TransMetaSegmentation (TMS), to address challenges in brain cell segmentation and metabolite allocation, respectively. We anticipate that this study will advance the understanding and treatment of neurological and genetic disorders.