Can we reverse Autism spectrum disorders? Maybe not just yet !
Impaired Amino Acid Transport at the Blood Brain Barrier
Is a Cause of Autism Spectrum Disorder
Opinion by Arit Ghosh, Ph.D.
In this study from last year the authors have definitely struck a chord with the communities affected by autism spectrum disorder. This research paper deals with a particular protein named Slc7a5 – a solute carrier protein that has been shown to transport amino acids (building blocks of protein molecules) across the blood brain barrier (BBB). This barrier is a highly selective (semi-permeable) membrane that seperates the circulating blood from the brain’s extracellular fluid in the central nervous system and may even be considered as a neuro-immune system. This barrier protects the brain from pathogens and infections by simply preventing bacteria and viruses from infiltration into the cerebro-spinal fluid (CSF). This also means that if an infection does arise in the brain, antibodies and several drugs cannot traverse this abyss into the brain via the BBB. During inflammation the BBB can become more permeable and susceptible towards infection and diseases such as toxoplasmosis, lyme disease, meningitis and syphilis can take hold. In this regard, branched chain amino acids are particularly important for brain function because they are involved both directly and indirectly in biochemical functions in the brain. The functions of BCAAs such as leucine, isoleucine and valine include protein synthesis, energy production as well as Glutamate compartmentalization (Glu – an excitatory amino acid neurotransmitter in the brain) as well as other neurotransmitters.
Dietary protein intake is high on BCAA and is not metabolized by the liver but is passed into systemic circulation leading to elevated plasma BCAA and eventual intake into the brain via the BBB. In humans, BCAAs have been shown to improve mental and physical prowess, whereas disease states such as bipolar disorder and other neurological diseases can be diminished or have their progression retarded via administering BCAA intakes [brain food?]. The only disorder that has thus been characterized due to excess BCAA intake is the rare genetic disorder – maple syrup urine disease (MSUD), while the molecular pathways behind it are largely unknown and not quite clear just yet.
As evidenced in this work [Slc7a5, BCAA and ASDs], the solute carrier protein – Slc7a5 was shown to be critical for transport of BCAAs across the blood brain barrier. The authors also show that mice knockouts of Slc7a5 have decreased protein translation, decreased social interaction as well as decreased motor activity. What this seems to suggest is that Slc7a5 is essential towards not only BCAA function and transport but also overall proteome (total protein in the cell/tissue/organism) function and a higher order activities in the brain. Also key brain functions lay on fine-tuning brain BCAA and large neutral amino acid levels and as such disbalance of this homeostasis may lead to autism spectrum disorder (ASD). Indeed as show in this study, Slc7a5 loss leads to ASD as well as motor dysfunctions in humans and in mice. But exogenous treatment with BCAAs however does not fully alleviate ASD and only shows partial rescue. This indeed suggests that BCAAs are not the sole component regulating ASD and there are other factors, which remain to be identified. Drugs acting on GABA (gamma-aminobutyric acid; an inhibitory neurotransmitter which reduces neuronal excitation and is responsible for muscle tone) transmission are considered promising avenues for treatments for ASD and epilepsy, therefore the authors suggest that understanding the molecular basis of how BCAAs may regulate GABAergic transmission can have relevance towards novel therapeutics for ASD and related neurological disorders. This is promising to a large extent but with future studies we do also need to understand two major questions in this field – A. Connecting the molecular basis and the significance of overexpression of BCAAs leading to the rare maple syrup disorder. B. Why does deletion of Slc7a5 lead to reduced translation and the subsequent phenotypes in mice? If the next set of follow up studies are able to address these queries, Slc7a5 holds great promise towards becoming a big player in novel therapeutics towards treatment of ASD and other neurological disorders.