ABSTRACTPropionic acidemia (PA) is an inborn error of metabolism (IEM) caused by mutations in the enzyme propionyl CoA carboxylase (PCC). It is characterized by the inability to break down branched chain amino acids and odd chain fatty acids, causing a buildup of toxic organic acids in blood. PA affects every organ in the body with particularly severe manifestations in the brain, like hyperammonemia, hypomyelination, seizures, cognitive impairments, optic nerve atrophy and autism spectrum disorders. Dietary management and liver transplantation have helped to ameliorate the acute expression of the disorder, but do not prevent the chronic toxicity that builds up in brain. Despite the severe brain manifestation of the disease, little is known about the mechanisms by which PA affects the nervous system.PCCA and PCCB, the two subunits required for a functional PCC enzyme, are both expressed not only in neurons but also in astrocytes. Using the two rodent genetic models of PA currently available, with mutations in PCCA, we have evaluated the involvement of astrocytes in the neuropathology of propionic acidemia. These mice exhibit cardiac pathology and hyperammonemia, similar to what is observed in patients with PA.We found that wild type (wt) astrocytes positively respond to treatment with L-Carnitine, a therapeutic approach commonly used in patients with PA, by improved survival and more efficient mitochondrial morphology. Transcriptome analysis from astrocytes derived from the wt or the mutant mice confirm that these astrocytes lack exons 3 and 4 like in the human mutations of PA. However, no other genes/exons were statistically significant with regards to differential expression between astrocytes derived from KO or from WT animals, suggesting that astrocytes in culture may be able to compensate the PCC deficiency.Histological analysis of neuronal and glial markers during brain development (TUJ1, MAP2 for neurons; nestin and Iba1 for glia) do not show significant alterations neither in distribution nor numbers of cells in the developing brain of the PCCA-/- mice. Analysis in the adult brain of mutant mice shows some variable degree of microgliosis but no indication of reactive astrocytes. No gross abnormalities were observed in cortex, hippocampus, striatum or cerebellum of adult brains of PCCA-/- mice, either.In summary, astrocytes from PCCA deficient mice show surprisingly little alterations both in vitro and in vivo. Our results evidence the need to further understand the effects of PA in brain cells to help develop potential new therapies that can preserve brain function in children affected by this devastating disease.HIGHLIGHTSAstrocytes detoxify ammonia in brain and may be affected by propionic acidemia, a disorder that causes hyperammonemia in brain.RNA seq of astrocytes in culture derived from PCCA mutant mice does not show effect in these cells.In vivo analysis of glial and neuronal cells also shows no difference in development or adult mutant miceAstrocytes may not be an adequate target of clinical therapies in this disorder
Autism-linked Cullin3 germline haploinsufficiency impacts cytoskeletal dynamics and cortical neurogenesis through RhoA signaling
