Highlights •TMLHE controls the neural stem cell (NSC) pool in the embryonic mouse neocortex •CPT1A and fatty acid mobilization from lipid droplets regulate the NSC pool •TMLHE deficiencies lead to increased symmetric differentiating division of NSCs •NSC defects under TMLHE deficiencies can be rescued by exogenous carnitine
Besides folic acid, another prenatal supplement could protect against a certain type of autism, according to research: carnitine. It is required for transport of fatty acids into mitochondria – that converts these fats into energy. Previous studies have shown that inherited mutations in a gene (called TMLHE) that is required for carnitine biosynthesis are strongly associated with risk for development of autism-spectrum disorders, but the basis for that association has been unclear – until now. The latest findings show that genetic defects in the body’s ability to manufacture carnitine might be associated with an increased risk of ASD because carnitine deficiency interferes with the normal processes by which neural stem cells promote and organize embryonic and fetal brain development.
“It’s very difficult to study neural stem cells in their complex natural environment,” Xie, Ph.D said. “But now we have a technology that makes such studies possible.” Vytas A. Bankaitis, Ph.D added: “..it allows us to identify specific neural stem cell defects that are invisible in the cell culture systems typically used by brain scientists. With regard to autism spectrum disorders, one has to consider the entire cellular environment, or niche.” They found that neural stem cells unable to produce carnitine don’t behave properly and are inappropriately depleted from the developing brain, but when genetically at-risk neural stem cells are supplied with carnitine from an outside source, they don’t have the same problems.
MOA: The autism-associated TMLHE gene encodes an enzyme that the body needs to manufacture carnitine. Autism risk mutations inactivate this gene and, in the absence of their own ability to produce carnitine and without adequate outside supplementation, neural stem cells become less efficient at self-renewal, ie , when they divide, neural stem cells produce 2 “daughter” cells, one of which should remain a neural stem cell and the other that should differentiate. Neural stem cells confronted with carnitine deficiency too often divide to produce 2 differentiated cells, thereby failing to resupply the developing brain with a cache of neural stem cells.
“Inborn errors in carnitine production cause significant issues in a cell type one would believe has to contribute to autism risk,” Bankaitis said. As the autism risk gene is located on the X chromosome and males have only one X chromosome (females have 2), they are at greater risk.
Some pregnant women might absorb enough carnitine from their diet so as to make normal enzyme function less important in the context of autism risk for their babies. High levels of carnitine are in red meat, and one of the best vegetarian sources is whole milk. Women who don’t ingest sufficient carnitine, however, might be placing their unborn child at risk.
As TMLHE is a recognized autism risk gene and its location on the chromosome is known, one possible first step for prevention is to test prospective mothers for TMLHE mutations before pregnancy. If a prospective mother is a carrier for the mutated autism risk gene, supplementation of her diet with carnitine before and during pregnancy could help ensure that a sufficient supply of the nutrient is available to the developing embryo and fetus, thus helping to offset the genetic defect.
It’s important to note that this particular prevention strategy will not apply to all cases of autism as other pathways are also in play. As many as 1000 genes might ultimately be found to relate to autism risk. Still, this limited preventive strategy could be significant as mutant TMLHE alleles are surprisingly common in the human population.
http://www.eurekalert.org/pub_releases/2016-01/tau-tar012116.php
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