Tesi etd-09262019-094921
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Tipo di tesi
Perfezionamento
Autore
RUTIGLIANO, GRAZIA
URN
etd-09262019-094921
Titolo
Beyond classical thyroid hormone.
3-iodothyronamine and the trace amine-associated receptor 1 in the cross-talk between thyroid and brain
Settore scientifico disciplinare
MED/25
Corso di studi
SCIENZE MEDICHE - Translational Medicine
Commissione
Membro Prof. IERVASI, GIORGIO
Membro Prof. RECCHIA, FABIO ANASTASIO
Membro Prof. GEMIGNANI, ANGELO
Membro Prof. BOGAZZI, FAUSTO
Membro Prof. RECCHIA, FABIO ANASTASIO
Membro Prof. GEMIGNANI, ANGELO
Membro Prof. BOGAZZI, FAUSTO
Parole chiave
- hypothyroidism
- levothyroxine
- triiodothyronine
- 3-iodothyronamine
- trace amine-associated receptor 1
- novel object recognition
- major mental disorders
- single-nucleotide variant
- Gs/adenylyl cyclase activation
- tridimensional homology model
Data inizio appello
22/11/2019;
Disponibilità
completa
Riassunto analitico
Hypothyroidism is one of the most common endocrine disorders. Once the diagnosis is formulated, guidelines from all professional societies recommend levothyroxine (L-T4) monotherapy as the treatment of choice, under the assumption that peripheral conversion provides the exact amount of triiodothyronine (T3) to tissues. However, ~ 15% of hypothyroid patients do not achieve a satisfactory functional level, despite attainment of biochemical euthyroidism. Persistent symptoms include depression, anxiety, and cognitive impairments. It has been argued that combined L-T4 & L-T3 therapy might provide a more physiological treatment plan, although meta-analytical evidence remains inconclusive. Recently, it emerged that 3-iodothyronamine (T1AM), one of the active thyroid hormone metabolites, has pro-learning and anti-amnestic effects, and modulates pain threshold, sleep pattern, and food intake. Its reduced availability might result in some cognitive/neuropsychiatric symptoms traditionally attributed to thyroid hormone. T1AM binds to the trace amine-associated receptor 1 (TAAR1), a G-protein coupled receptor with a putative role in neurotransmission. The human gene for TAAR1 maps to locus 6q23, within a region associated with major mental disorders.
Here, we performed a cross-sectional study of a sample of hypothyroid patients. We tested the correlation between clinical/biochemical variables and neurocognitive and psychometric variables. We found inverse relationships between: thyroid-stimulating hormone (TSH) levels and executive functions; circulating levels of fT4 and fT3 and perception of sleepiness. Also, circulating levels of fT3 positively correlated with personal drive. Moreover, hypothyroid patients displayed higher anxiety levels than the general population.
We developed a pharmacological mouse model of hypothyroidism. Hypothyroid mice were administered various combinations of classical and non-classical thyroid hormones, i.e., L-T4, L-T4 & L-T3, L-T4 & T1AM, T1AM. Groups were compared with respect to hippocampus-dependent memory, locomotor activity, depression- and anxiety- related behaviours. Hypothyroid mice displayed significantly impaired hippocampus-dependent memory, which was almost fully normalized by L-T4 monotherapy. A larger improvement was observed upon L-T4 & T1AM replacement, while T1AM did not induce any effect per se. Hippocampus-dependent memory remained disrupted under L-T4 & L-T3, possibly due to thyrotoxicosis. No differences were found in anxiety, depression, and locomotion levels.
Our final aim was to identify and functionally characterize TAAR1 variants in patients suffering from major mental disorders. We detected 13 missense variants in TAAR1 coding region, with a significant enrichment in patients as compared to healthy controls (11 vs 1, 1 variant in both groups). Based on in silico predictions, we selected 3 variants - R23C, Y131C, C263R – for in vitro characterization. In cells co-transfected with wild type and mutated TAAR1 we observed a significant reduction of cell surface expression and dampening of ligand-activated Gs/adenylyl cyclase signalling. R23C, Y131C, and C263R are rare in the general population and map to functionally important highly conserved positions in the protein.
Our findings challenge the common view that thyroid replacement is easily accomplished in all hypothyroid patients. Response variability may relate to the complexity of the homeostatic control of thyroid status, operating at several levels of spatial and temporal organization. T1AM appears as a novel stakeholder in central effects of thyroid hormone, probably through TAAR1. Sub-functional TAAR1, either because of reduced availability of its endogenous ligand, or due to missense mutations, may represent a vulnerability factor for the development of mental disturbances.
Here, we performed a cross-sectional study of a sample of hypothyroid patients. We tested the correlation between clinical/biochemical variables and neurocognitive and psychometric variables. We found inverse relationships between: thyroid-stimulating hormone (TSH) levels and executive functions; circulating levels of fT4 and fT3 and perception of sleepiness. Also, circulating levels of fT3 positively correlated with personal drive. Moreover, hypothyroid patients displayed higher anxiety levels than the general population.
We developed a pharmacological mouse model of hypothyroidism. Hypothyroid mice were administered various combinations of classical and non-classical thyroid hormones, i.e., L-T4, L-T4 & L-T3, L-T4 & T1AM, T1AM. Groups were compared with respect to hippocampus-dependent memory, locomotor activity, depression- and anxiety- related behaviours. Hypothyroid mice displayed significantly impaired hippocampus-dependent memory, which was almost fully normalized by L-T4 monotherapy. A larger improvement was observed upon L-T4 & T1AM replacement, while T1AM did not induce any effect per se. Hippocampus-dependent memory remained disrupted under L-T4 & L-T3, possibly due to thyrotoxicosis. No differences were found in anxiety, depression, and locomotion levels.
Our final aim was to identify and functionally characterize TAAR1 variants in patients suffering from major mental disorders. We detected 13 missense variants in TAAR1 coding region, with a significant enrichment in patients as compared to healthy controls (11 vs 1, 1 variant in both groups). Based on in silico predictions, we selected 3 variants - R23C, Y131C, C263R – for in vitro characterization. In cells co-transfected with wild type and mutated TAAR1 we observed a significant reduction of cell surface expression and dampening of ligand-activated Gs/adenylyl cyclase signalling. R23C, Y131C, and C263R are rare in the general population and map to functionally important highly conserved positions in the protein.
Our findings challenge the common view that thyroid replacement is easily accomplished in all hypothyroid patients. Response variability may relate to the complexity of the homeostatic control of thyroid status, operating at several levels of spatial and temporal organization. T1AM appears as a novel stakeholder in central effects of thyroid hormone, probably through TAAR1. Sub-functional TAAR1, either because of reduced availability of its endogenous ligand, or due to missense mutations, may represent a vulnerability factor for the development of mental disturbances.
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