Scientific Understanding of Consciousness
Autism Therapy may involve Signaling Pathway that Controls Protein Synthesis
Science 11 Mar 2016:Vol. 351, Issue 6278, pp. 1153-1154
Unraveling a pathway to autism
J. Peter H. Burbach
Brain Center Rudolf Magnus, Department of Translational Neuroscience, University Medical Center Utrecht, Netherlands.
Autism spectrum disorders (ASDs) are a heterogeneous group of neurodevelopmental disorders with shared symptoms in the area of communication and language, restricted interests, and stereotyped and social behaviors. Causes lie in perturbations of brain development, which can be manifold, but genetic factors are prominent among these. Genetic studies have pointed to hundreds of causative or susceptibility genes in ASD, making it difficult to find common underlying pathogenic mechanisms. Careful dissection of molecular and cellular mechanisms are needed to define the molecular targets that can translate into therapeutic strategies. Research studies have uncovered defects in a molecular machinery of a genetic ASD mouse model. This allowed the researchers to design specific chemical interventions that relieve cellular and behavioral autistic-like features. In addition, a channelopathy in neurons may predispose to autism. The discoveries raise hope for developing new drugs that help patients with ASD.
Current thinking about pharmacological therapies for ASDs has been stimulated by two scientific milestones. One major advance has been the large number of genes associated with risk for autism (from human genetic studies). This has extended the clinical notion that ASDs include heterogeneous conditions ranging from severe intellectual disability to high-functioning forms. Furthermore, identified gene variants in ASDs all appear to be rare, and recurrence is very low (less than 1%) in sporadic cases. However, a number of syndromes with autistic-like features—in addition to fragile X and Rett syndromes—have been recognized. One of these is the Phelan-McDermid syndrome.
Considering the human genetics of ASDs, the spectrum of properties of proteins encoded by ASD genes can be aggregated in a number of molecular and cellular functions. Thus, protein synthesis and degradation, signal transduction, transcription, and synaptic transmission emerge as major cellular processes from which ASDs may originate. These processes are not independent of each other. For example, transcription, translation, and degradation together control the quantity and quality of the total pool of proteins of the cell. Signal transduction couples extracellular chemical signals, such as neurotransmitters and growth factors, to intracellular responses including protein synthesis and degradation, and transcription. These are all essential activity-dependent pathways that remain highly dynamic in adult stages. At an integrated level, these cellular pathways are apparent in biological functions relevant for ASDs, in particular synaptogenesis, axon guidance, dendritic and spine morphology, and synaptic plasticity. This has led to the hypothesis that abnormal synaptic homeostasis could play a key role in the pathogenesis of ASDs.
The other milestone in the field is the notion that neurodevelopmental defects are not necessarily permanent, but may be reversible. There has been a long-standing view that neurodevelopmental disorders are congenital inborn errors of brain development that leave the patient with irreversible defects. This traditional view was first challenged by the reactivation of a silenced gene encoding methyl CpG-binding protein 2 (MeCP2) in a mouse model of Rett syndrome. Induction of Mecp2 expression dramatically reversed behavioral and electrophysiological abnormalities in developing and adult mice. Selective reversal of abnormalities was also observed in other ASD models. For example, phenotypes in mice lacking the gene encoding the protein tuberous sclerosis 1 (TSC1) could be reversed by the small molecule rapamycin. Rapamycin blocks mammalian/mechanistic target of rapamycin complex 1 (mTORC1), which controls protein synthesis. The TSC1-TSC2 complex controls mTORC1 activity. In mouse models of fragile X syndrome [mice that lack the gene encoding fragile X mental retardation protein 1 (FMRP1)], treatment with an antagonist of the metabotropic glutamate receptor 1/5 class (mGluR1/5) also reversed disease characteristics. Signaling by mGluR1/5 is coupled to synaptic response involving FMRP1. Moreover, insulin-like growth factor I has been successfully used to ameliorate autistic-like phenotypes in mouse models of Rett syndrome and Phelan-McDermid syndrome. SHANK3 is the prime gene culprit causing the latter disorder. Interestingly, selective rescue of autistic-like phenotypes in a mouse model was established by reexpression of Shank3.
The results suggest that small molecules that activate AKT or inhibit CLK2 may be used to adjust the activity of a critical signaling pathway in ASDs. Experimental work reversed abnormalities at the molecular level (AKT phosphorylation) and cellular level (density of dendritic spines; miniature excitatory postsynaptic currents) with such compounds in Shank3-deficient neurons, and also reversed abnormal social behaviors in Shank3-deficient mice. These are important proofs of principle for drug targets to be taken further in the direction of drug development.
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