SSADH [Neurosurgery Wiki]

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====== SSADH ======

[[SSADH]], or succinic semialdehyde dehydrogenase, is an [[enzyme]] that plays a critical role in the [[metabolism]] of the [[neurotransmitter]] gamma-aminobutyric acid ([[GABA]]) in the brain. GABA is a major inhibitory neurotransmitter that helps regulate neuronal activity in the brain.

SSADH catalyzes the final step in the metabolism of GABA, converting [[succinic semialdehyde]] (SSA) to [[succinate]]. Mutations in the [[gene]] that encodes for SSADH can result in a rare genetic disorder called [[SSADH deficiency]]. This disorder is characterized by a buildup of SSA in the brain and other tissues, which can lead to seizures, developmental delays, intellectual disability, and other neurological symptoms.

Research has also suggested that alterations in SSADH activity may be involved in the development of certain neurological and psychiatric disorders. For example, decreased SSADH activity has been associated with an increased risk of developing schizophrenia, and changes in SSADH expression have been observed in the brains of individuals with autism spectrum disorders.

Understanding the role of SSADH in the brain and its potential involvement in various neurological and psychiatric disorders is an active area of research. New therapies and interventions targeting SSADH activity may hold promise for the treatment of these disorders.
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Cell populations with differing proliferative, stem-like, and tumorigenic states co-exist in most tumors and especially malignant gliomas. Whether metabolic variations can drive this heterogeneity by controlling dynamic changes in cell states is unknown. Metabolite profiling of human adult glioblastoma stem-like cells upon loss of their tumorigenicity revealed a switch in the catabolism of the GABA neurotransmitter toward enhanced production and secretion of its by-product GHB (4-hydroxybutyrate). This switch was driven by succinic semialdehyde dehydrogenase (SSADH) downregulation. Enhancing GHB levels via SSADH downregulation or GHB supplementation triggered cell conversion into a less aggressive phenotypic state. GHB affected adult glioblastoma cells with varying molecular profiles, along with cells from pediatric pontine gliomas. In all cell types, GHB acted by inhibiting α-ketoglutarate-dependent Ten-eleven Translocations (TET) activity, resulting in decreased levels of the 5-hydroxymethylcytosine epigenetic mark. In patients, low SSADH expression was correlated with high GHB/α-ketoglutarate ratios and distinguished weakly proliferative/differentiated glioblastoma territories from proliferative/non-differentiated territories. The findings support the active participation of metabolic variations in the genesis of tumor heterogeneity
((El-Habr EA, Dubois LG, Burel-Vandenbos F, Bogeas A, Lipecka J, Turchi L, Lejeune FX, Coehlo PL, Yamaki T, Wittmann BM, Fareh M, Mahfoudhi E, Janin M, Narayanan A, Morvan-Dubois G, Schmitt C, Verreault M, Oliver L, Sharif A, Pallud J, Devaux B, Puget S, Korkolopoulou P, Varlet P, Ottolenghi C, Plo I, Moura-Neto V, Virolle T, Chneiweiss H, Junier MP. A driver role for GABA metabolism in controlling stem and proliferative cell state through GHB production in glioma. Acta Neuropathol. 2017 Apr;133(4):645-660. doi: 10.1007/s00401-016-1659-5. Epub 2016 Dec 28. PMID: 28032215; PMCID: PMC5348560.)).
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Modulation of [[SSADH]] was shown to impact [[glioma cell]] properties, such as [[proliferation]], self-renewal and [[tumorigenicity]]. 

The purpose of a study by Piperi et al. was to investigate the clinical significance of [[SSADH]] expression in human [[glioma]]s. Using [[public single-cell RNA-sequencing data]] from glioma surgical resections, Piperi et al. initially grouped [[cancer cell]]s according to [[ALDH5A1]] (Aldehyde dehydrogenase 5 family member A1) expression, which encodes [[SSADH]]. [[Gene ontology enrichment analysis]] of genes differentially expressed between cancer cells expressing high or low levels of ALDH5A1, highlighted enrichment in genes implicated in the cell [[morphogenesis]] and motility. In [[glioblastoma cell lines]], [[ALDH5A1]] [[knockdown]] inhibited [[cell proliferation]], induced [[apoptosis]], and reduced their migratory potential. This was accompanied by a reduction in the [[mRNA]] levels of the adherens junction molecule [[ADAM-15]] and deregulation in the expression of EMT biomarkers, with increased [[CDH1]] and decreased [[vimentin]] [[mRNA]] levels. Evaluation of SSADH expression in a cohort of 95 gliomas using [[immunohistochemistry]] showed that [[SSADH]] expression was significantly elevated in cancer tissues compared to normal brain tissues, without any significant correlation with clinicopathological characteristics. In summary, data show that SSADH is upregulated in [[glioma]]  irrespective of the histological grade, and its expression sustains [[glioma cell motility]]
((Piperi C, Saurty-Seerunghen MS, Levidou G, Sepsa A, Trigka EA, Klonou A, Markouli M, Strepkos D, Spyropoulou A, Kanakoglou DS, Lakiotaki E, Karatrasoglou EA, Boviatsis E, El-Habr EA, Korkolopoulou P. Glioma Cells Expressing High Levels of ALDH5A1 Exhibit Enhanced Migration Transcriptional Signature in Patient Tumors. Neurotherapeutics. 2023 Mar 28. doi: 10.1007/s13311-023-01354-8. Epub ahead of print. PMID: 36976494.))