TS-EUROTRAIN: A European-Wide Investigation and Training Network on the Etiology and Pathophysiology of Gilles de la Tourette Syndrome

Abstract

Gilles de la Tourette Syndrome (GTS) is characterized by the presence of multiple motor and phonic tics with a fluctuating course of intensity, frequency, and severity. Up to 90% of patients with GTS present with comorbid conditions, most commonly attention-deficit/hyperactivity disorder (ADHD), and obsessive-compulsive disorder (OCD), thus providing an excellent model for the exploration of shared etiology across disorders. TS-EUROTRAIN (FP7-PEOPLE-2012-ITN, Grant Agr.No. 316978) is a Marie Curie Initial Training Network (http://ts-eurotrain.eu) that aims to elucidate the complex etiology of the onset and clinical course of GTS, investigate the neurobiological underpinnings of GTS and related disorders, translate research findings into clinical applications, and establish a pan-European infrastructure for the study of GTS. This includes the challenges of (i) assembling a large genetic database for the evaluation of the genetic architecture with high statistical power; (ii) exploring the role of gene-environment interactions including the effects of epigenetic phenomena; (iii) employing endophenotype-based approaches to understand the shared etiology between GTS, OCD, and ADHD; (iv) establishing a developmental animal model for GTS; (v) gaining new insights into the neurobiological mechanisms of GTS via cross-sectional and longitudinal neuroimaging studies; and (vi) partaking in outreach activities including the dissemination of scientific knowledge about GTS to the public. Fifteen partners from academia and industry and 12 PhD candidates pursue the project. Here, we aim to share the design of an interdisciplinary project, showcasing the potential of large-scale collaborative efforts in the field of GTS. Our ultimate aims are to elucidate the complex etiology and neurobiological underpinnings of GTS, translate research findings into clinical applications, and establish Pan-European infrastructure for the study of GTS and associated disorders.

Keywords: Gilles de la Tourette Syndrome; Initial Training Network; animal models; etiology; genetics; neuroimaging; tourette disorder.

Figure 1

Network of reported candidate genes associated with GTS. This image was produced (by JW) with Ingenuity pathway analysis software and shows how the proteins encoded by the candidate genes reported to be associated with GTS are linked with each other. Please see legend for description of what each symbol and color represents. ADRA1A, adrenoceptor alpha 1A; ADRA2A, adrenoceptor alpha 2A; ADRA2C, adrenoceptor alpha 2C; BTBD9, BTB (POZ) domain containing 9; CaMKII, calcium/calmodulin-dependent protein kinase II; CCT8, chaperonin containing TCP1, subunit 8 (theta); CNTNAP2, contactin-associated protein-like 2; COMT, catechol-O-methyltransferase; CTNNA3, catenin (cadherin-associated protein), alpha 3; CTTNBP2, contactin binding protein 2; CUL3, cullin 3; DBH, dopamine beta-hydroxylase (dopamine beta-monooxygenase); DLGAP3, discs; large (Drosophila) homolog-associated protein 3; DRD1, dopamine receptor D1, DRD2, dopamine receptor D2, DRD3, dopamine receptor D3, DRD4, dopamine receptor D4, ERK 1/2, extracellular signal-regulated kinases 1/2; HDC, histidine decarboxylase, HNF4A, hepatocyte nuclear factor 4 alpha; HTR2A, 5-hydroxytryptamine (serotonin) receptor 2A; G protein-coupled; HTR2C, 5-hydroxytryptamine (serotonin) receptor 2C; G protein-coupled; IL1RN, interleukin 1 receptor antagonist; KCNE1, potassium channel voltage gated subfamily E regulatory beta subunit 1; KCNE2, potassium channel, voltage gated subfamily E regulatory beta subunit 2; LHX6, LIM homeobox 6; MAOA, monoamine oxidase A; MRPL21, mitochondrial ribosomal protein L21; MRPL3, mitochondrial ribosomal protein L3; MYC, v-myc avian myelocytomatosis viral oncogene homolog; NLGN4X, neuroligin 4, X-linked; NRXN1, neurexin 1; OFCC1, orofacial cleft 1 candidate 1; PPARA, peroxisome proliferator-activated receptor alpha; RCAN1, regulator of calcineurin 1; PSEN1/2, presenilin 1/2; SLC1A3, solute carrier family 1 (glial high affinity glutamate transporter), member 3; SLC6A3, solute carrier family 6 (neurotransmitter transporter); member 3; SLC6A4, solute carrier family 6 (neurotransmitter transporter), member 4, SLITRK1, SLIT, and NTRK-like family, member 1; TPH2, tryptophan hydroxylase 2; YWHAB, tyrosine 3-monooxygenase/tryptophan 5-monooxygenase activation protein, beta.

Figure 2

Major neurotransmitter pathways related to GTS pathophysiology. Simplified schematic illustration of the major neurotransmitter systems reported and hypothesized to be involved in GTS pathophysiology. Other neuromodulatory systems that have been implicated include the cholinergic, histaminergic, and endocannabinoid systems. The figure was adapted based on information from Singer (2013) and Schumann et al. (2010). (5-HT, serotonergic; ACC, anterior cingulate cortex; Amygd, amygdala; Caud, Caudate nucleus; DA, dopaminergic; DR, dorsal raphe nucleus; GABA, gamma-aminobutyric acid; Glu, glutamatergic; GP, globus pallidus; MCC, mid cingulate cortex; NAcc, nucleus accumbens; OFC, orbitofrontal cortex; PCC, posterior cingulate cortex; PFC, prefrontal cortex; Put, putamen; RN, raphe nucleus; SMA, supplementary motor area; SN, substantia nigra; Tha, thalamus; VM-PFC, ventromedial prefrontal cortex; VTA: ventral tegmental area).