ETA2024 Poster Presentations Intracellular effects of TH (10 abstracts)
Brain abnormalities in young mice harboring combined NKX2-1 and PAX8 gene mutations
Antonia Giacco 1 , Stefania Iervolino 1 , Federica Cioffi 1 , Teresa Peluso 2 , Giovanna Mercurio 3 , Luca Roberto 4 , Valeria de Rosa 5 , Mariarosaria Cammarota 5 , Silvia Varricchio 6 , Stefania Staibano 6 , Francesca Boscia 5 , Lorella Maria Teresa Canzoniero 7 , Mario De Felice 4 , Concetta Ambrosino 1 , Maria Moreno 8 & Elena Silvestri 9
1University of Sannio, Benevento; Dep. Science and Technology, Benevento, Italy; 2Università Degli Studi del Sannio, Scienze e Tecnologie, Benevento, Italy; 3University of Sannio, Department of Sciences and Technologies, Benevento, Italy; 4Istituto di Ricerche Genetiche G.Salvatore, Biogem S.C.Ar.L, Ariano Irpino, Avellino, Italia; 5Federico Ii University of Naples, Division of Pharmacology, Department of Neuroscience, Italy; 6Federico Ii University of Naples, Department of Advanced Biomedical Sciences, Pathology Section, Italy; 7Dipartimento di Scienze e Tecnologie (Dst), Università Degli Studi del Sannio di Benevento, Italy; 8Universitá Sannio, Benevento, Italy; 9University of Sannio, Benevento, Dep. Science and Technology, Benevento, Italy
Objectives: It has been extensively demonstrated that hypothyroidism can profoundly disrupt the ontogenesis and functions of the brain, leading to impairments in cognitive abilities and psychosis. This can occur due to an imbalance induced by hypothyroidism in the physiologically programmed formation of neurons within specific time windows and brain regions. It is unclear whether mutations in the mammalian thyroid morphogenic genes Pax8 and Nkx2-1 may directly or indirectly collaborate in causing adult brain abnormalities. It is also unknown if these potential changes may involve the mitochondrial compartment. Such uncertainty primarily stems from the fact that mitochondria are organelles highly susceptible to alterations in thyroid activity and the fundamental basis for brain functions.
Methods: In this study, we examined brain features in 3 month-old single or double heterozygotes for Nkx2-1- and Pax8-null mutations (DHTP) mice under different human-like dysthyroidisms. We focused on potential alterations of specific neurotransmitter systems, expression of markers of pre- and post-synaptic function and, given the physio-pathological role mitochondria have in controlling the bioenergetic status of neurons, of mitochondrial dynamics and oxidative balance. An integrated approach was employed by combining transcriptomic, proteomic, functional and histology techniques.
Results: Compared to Wt controls, DHTP mice, bearing both systemic and brain hypothyroidism, showed altered expression of synaptic markers, generic and cholinergic (corroborated by immunohistochemistry in caudate, putamen, hippocampus, and basal forebrain) and glutamatergic-ones. Addittionally, they showed reduced expression of key proteins related to synaptic plasticity potency and several glutamate receptor isoforms. DHTP mice brains also exhibited imbalanced mitochondrial dynamics. Nkx2-1+/- mice displayed dopaminergic neuron-specific alterations, morphologically, more evident in the substantia nigra of DHTP mice. Nkx2-1+/- mice also exhibited enhanced mitochondrial biogenesis and oxidative capacity likely as a global response of brain to Nkx2-1 haploinsufficiency and/or to their elevated T3 circulating levels. Pax8+/- euthyroid mice showed reduced transcription of both tyrosine hydroxylase and dopamine transporter, indicating dopaminergic dysfunction, possibly at an early stage, but consistent with observed deregulated glucose homeostasis in such animals.
Conclusions: Overall, this study provides new insights into the impact of Pax8 and NKx2-1 haploinsufficiency on various neuroanatomical, molecular, and neurochemical aspects of the brain. These findings offer new perspectives for targeting brain alterations and dysmetabolism in managing overt and subclinical thyroid dysfunctions, potentially preventing or counteracting neurological abnormalities that may predispose to dementia, cognitive disturbances, and behavioral alterations.
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Endocrine Abstracts
ISSN 1470-3947 (print) | ISSN 1479-6848 (online)
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