Autism and the endoplasmic reticulum

By identifying a key signalling defect within a specific membrane structure in all cells, researchers believe they have found both a possible reliable biomarker for diagnosing certain forms of autism and a potential therapeutic target.

J. Jay Gargus, MD, and Ian Parker, MD, University of California at Irvine Center for Autism Research & Translation, Irvine, California, and colleagues examined skin biopsies of patients with fragile X syndrome and tuberous sclerosis 1 and 2.

They discovered that a cellular calcium signalling process involving the inositol trisphosphate receptor was very much altered.

This IP3R functional defect was located in the endoplasmic reticulum, which is among the specialised membrane compartments in cells called organelles, and may underpin cognitive impairments -- and possibly digestive and immune problems -- associated with autism.

There are no current, reliable diagnostic biomarkers for autism spectrum disorder (ASD). Genetic research has identified hundreds of genes that are involved, which impedes diagnosis and, ultimately, drug development. There simply may be too many targets, each with too small an effect.

Many of these genes associated with ASD, however, have been found to be part of the same signalling pathway, and multiple defects in this pathway may converge to produce a large functional change.

The researchers detected such a convergence in the IP3R calcium channel in an organelle called the endoplasmic reticulum. According to Dr. Gargus, diseases of the organelles are an emerging field in medicine, with several well-recognised neurological ailments linked to the mitochondria and lysosomes.

The IP3R controls the release of calcium from the ER. In the brain, calcium is used to communicate information within and between neurons, and it activates a host of other cell functions, including ones regulating learning and memory, neuronal excitability and neurotransmitter release - areas known to be dysfunctional in ASD.

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Schmunk G, Boubion BJ, Smith IF, Parker I, Gargus JJ. Shared functional defect
in IP(3)R-mediated calcium signaling in diverse monogenic autism syndromes.
Transl Psychiatry. 2015 Sep 22;5:e643.

Abstract

Autism spectrum disorder (ASD) affects 2% of children, and is characterized by impaired social and communication skills together with repetitive, stereotypic behavior. The pathophysiology of ASD is complex due to genetic and environmental heterogeneity, complicating the development of therapies and making diagnosis challenging. Growing genetic evidence supports a role of disrupted Ca²⁺ signaling in ASD. Here, we report that patient-derived fibroblasts from three monogenic models of ASD-fragile X and tuberous sclerosis TSC1 and TSC2 syndromes-display depressed Ca²⁺ release through inositol trisphosphate receptors (IP₃Rs). This was apparent in Ca²⁺ signals evoked by G protein-coupled receptors and by photoreleased IP₃ at the levels of both global and local elementary Ca²⁺ events, suggesting fundamental defects in IP₃R channel activity in ASD. Given the ubiquitous involvement of IP₃R-mediated Ca²⁺ signaling in neuronal excitability, synaptic plasticity, gene expression and neurodevelopment, we propose dysregulated IP₃R signaling as a nexus where genes altered in ASD converge to exert their deleterious effect. These findings highlight potential pharmaceutical targets, and identify Ca²⁺ screening in skin fibroblasts as a promising technique for early detection of individuals susceptible to ASD.