Cellular and molecular outcomes of glutamine supplementation in the brain of succinic semialdehyde dehydrogenase‐deficient mice

Abstract

Succinic semialdehyde dehydrogenase deficiency (SSADHD) manifests with low levels of glutamine in the brain, suggesting that central glutamine deficiency contributes to pathogenesis. Recently, we attempted to rescue the disease phenotype of aldh5a1−/− mice, a murine model of SSADHD with dietary glutamine supplementation. No clinical rescue and no central glutamine improvement were observed. Here, we report the results of follow‐up studies of the cellular and molecular basis of the resistance of the brain to glutamine supplementation. We first determined if the expression of genes involved in glutamine metabolism was impacted by glutamine feeding. We then searched for changes of brain histology in response to glutamine supplementation, with a focus on astrocytes, known regulators of glutamine synthesis in the brain. Glutamine supplementation significantly modified the expression of glutaminase (gls) (0.6‐fold down), glutamine synthetase (glul) (1.5‐fold up), and glutamine transporters (solute carrier family 7, member 5 [slc7a5], 2.5‐fold up; slc38a2, 0.6‐fold down). The number of GLUL‐labeled cells was greater in the glutamine‐supplemented group than in controls (P < .05). Reactive astrogliosis, a hallmark of brain inflammation in SSADHD, was confirmed. We observed a 2‐fold stronger astrocyte staining in mutants than in wild‐type controls (optical density/cell were 1.8 ± 0.08 in aldh5a1−/− and 0.99 ± 0.06 in aldh5a1+/+; P < .0001), and a 3‐fold higher expression of gfap and vimentin. However, glutamine supplementation did not improve the histological and molecular signature of astrogliosis. Thus, glutamine supplementation impacts genes implicated in central glutamine homeostasis without improving reactive astrogliosis. The mechanisms underlying glutamine deficiency and its contribution to SSADHD pathogenesis remain unknown and should be the focus of future investigations.

Postmortem Analyses in a Patient With Succinic Semialdehyde Dehydrogenase Deficiency (SSADHD): II. Histological, Lipid, and Gene Expression Outcomes in Regional Brain Tissue

“…24 For the first time, we have shown the presence of astrogliosis in selected brain regions of a patient with SSADHD, confirming earlier studies in the brain of null mice. 6,15 Reactive astrogliosis was present in the patient's cortex, subcortical white matter, and hippocampus. Although gliosis in and of itself is not specific for any specific pathologic entity, it is a useful marker for subtle or early pathologic changes and can also reflect chronic injury to a particular brain region.…”

“…In the current report, we extend these metabolic studies to examine histopathology, lipid content, and gene expression in the same tissues. The following hypotheses were evaluated: (1) patient cortex/hippocampus would reveal astrogliosis 6,15 ; (2) ethanolamine glycerophospholipid content in patient brain sections would be decreased 16,17 ; and (3) downregulation of GABAergic/glutamatergic receptor subunits would be observed).…”

Mitochondrial-related genes PDK2, CHDH, and ALDH5A1 served as a diagnostic signature and correlated with immune cell infiltration in ulcerative colitis

“…Evidence suggests that the depletion of ALDH5A1 can result in mitochondrial dysfunction, including the impairment of γ-aminobutyric acid (GABA) metabolism [ 36 ]. Research has demonstrated that a decrease in ALDH5A1 may result in mitochondrial dysfunction, characterized by diminished ATP production, heightened oxidative stress, and impaired mitochondrial dynamics, ultimately culminating in cellular apoptosis and inflammatory responses [ 37 ]. Within the context of UC, the reduction of ALDH5A1 can exacerbate mitochondrial dysfunction and oxidative stress, thereby contributing to the advancement of the disease.…”

Author Response: Novel ALDH5A1 Variants and Genotype: Phenotype Correlation in SSADH Deficiency

“…In vivo exposure of the brain to GHB triggers intracellular calcium spikes, which has long-term impacts on astrocyte function and might contribute to the well-known epileptogenic activity of GHB. 2 Other studies 3 —including our own—underscore the role of activated glial cells (reactive astrogliosis) and ensuing GABA-glutamine-glutamate cycle dysfunction in the phenotype of experimental ADLH5A1 deficiency (aldh5a1-deficient mice). Earlier studies in this model presented evidence for glial dysfunction and reduced glutamate/glutamine cycling.…”