Tourette’s Syndrome: Molecular Basis

Author: Will Bowman

A diagram of where neurexin interacts at the synapse.

A variety of molecular signals have been investigated for roles in Tourette’s Syndrome, either as an indicator of tic severity or as a causative agent. These studies range from neurotransmitter levels, to protein expression, to effects of immune response.

Across studies from several age groups, it has been found that levels of GABA in the sensorimotor cortex and supplementary motor area are significantly different to the respective age related control, but vary between individual studies. GABA was found to be significantly lowered in the Anterior cingulate cortex compared to same age controls, however GABA levels were not found to correlate to severity of tics. This data does suggest Tourette’s related abnormalities in GABAnergic systems, though not as a directly causative role. Broad differences across studies are historically different in observed GABA levels, however most of these studies are not comparable due to inconsistencies with methodology, explored brain regions, or medications present in the patients (Freed, R. et al. 2016)

Metabolite concentrations in cortico-striato-thalamo-cortical circuits were compared to that of healthy persons. Small changes in glutamine concentration were reported in literature, showing increased glutamine to glutamate ratios in supplementary motor areas. The study suggests that there is abnormal glutamate – glutamine cycling as well as increased supplementary motor area activation (Fan, S. et al. 2017).

Protein expression has also been explored as it relates to Tourette’s Syndrome. Synapse formation and properties are regulated by signalling proteins known as neurexins, expressed in the brain. Mutations encoding these signal proteins are implicated in Tourette’s Syndrome. These proteins are presynaptic and interact with a variety of ligands, both pre- and post-synaptically, which then interact with other intra- and extra-cellular signalling proteins in a dynamic network. Neurons are constantly forming new synapses as the connections naturally deteriorate over time. Deletion of NRXN1, which encodes neurexin, has been associated with neurological disorders, however this is thought to be a relatively rare causative factor. Furthermore, it is not known whether or not these mutations are sufficient for a disorder, or only modulating the severity. In mouse models, neurexin mutations were demonstrated to have implications in behavioral impairments such as decreased pre-pulse inhibition and impaired nest building, which are comparative to other Tourette’s stereotypies in animal models. Human studies have found neurexin loss of function mutations can have considerable synaptic impairment, implying a dysregulation of neurotransmitter release (Südhof, T.. 2017).

Immunoglobulin have been implicated in a causative role of Tourette’s Syndrome, which can be conferred across species. Anti-neuronal antibodies have been detected in serologic studies in affected children. In a study rats who were injected with serum from affected children were found to exhibit Tourette’s like symptoms for several days after microinfusion. A second study was then conducted to isolate gamma immunoglobulins from the original serum, and then microinfused into the rats. Gamma immunoglobulins from affected children are known to bind to neurons in the basal ganglia, which is thought to have a role in the pathology of Tourette’s Syndrome. Transferable factors in serum can transmit the stereotypic movement and tics associated with the disorder when microinfused into rat striata. Such effects can also be produced by infusion of dopaminergic agents. Presence of an anti-neuronal antibody implies the local synthesis of such factors, as the cannot cross the blood brain barrier, likely from B-lymphocytes which can cross the barrier. It is predicted that these immunoglobulins are incorporated into the immune response of these lymphocytes and then released as part of an autoimmune like response within the brain and cause damage (Hallet et al. 2000).

As further work continues, exploratory studies using cerebrospinal fluid as a medium to detect differential metabolite concentrations was conducted to test the plausibility of such a experiment. In this work, chemokine, cytokine, lymphocyte, and immunoglobulin markers were studied. However, no statistically significant or consistent chemokine/cytokine, lymphocyte subset, or immunoglobulin abnormalities were found. As this was an exploratory study, a very small sample size was used and therefore bears repetition. Despite this, the feasibility of using cerebrospinal fluid markers was proven, and may be useful to investigate other potential agents for their relevance to Tourette’s Syndrome (Pranzatelli, M, 2017).




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