Annunci

Two positions for Master Thesis available from November 2021 (begining may also be in January 2022) at the Cellular and Developmental Neurobiology Lab of the University of Trieste, Department of Life Sciences

Contacts: prof. Enrico Tongiorgi tongi@units.it; Skype: enricotongiorgi

Website: https://dsv.units.it/it/ricerca/ambiti/gruppi/18224

Rett syndrome (RTT, OMIM 312750), a neurodevelopmental dominant X-linked disorder, is the leading cause of mental retardation in females affecting about 1/10,000 newborn girls. In 90-95% cases, RTT is caused by mutations in the gene encoding methyl-CpG-binding protein 2 (MeCP2), a transcriptional regulator involved also in chromatin reorganization. RTT is characterized by apparently normal development for 6–18 months, followed by a period of regression with loss of purposeful hand use, deceleration of head growth associated with neuronal atrophy, motor deficits, respiratory abnormalities and seizures. The demonstration that RTT neurological defects can be rectified by re-expressing Mecp2 gene in adult mice, together with the lack of neuronal loss, indicated that RTT is not an irrevocable disease. However, approaches aiming to restore the normal gene dosage are far from being achieved and pharmacological therapies for RTT are not yet available, besides anti-epileptic drugs.

 The laboratory of prof. Enrico Tongiorgi at the University of Trieste has undertaken a multi-year project to identify FDA-approved drugs that can repurposed in RTT. They have already demonstrated that the antidepressant mirtazapine can rescue neuronal atrophy, Glutamate/GABA imbalance, dendritic spines abnormalities, synapse loss and restore normal breath rhythm in male MeCP2-KO mice (Bittolo et al., 2016 - http://dx.doi.org/10.1038/srep19796). In addition, they demonstrated a protective effect of mirtazapine in adult female heterozygous mice in which motor deterioration was prevented and somatosensory problems were corrected, as well as in adult RTT patients in which behavioural, mood, and motor alterations were improved (Flores-Gutierrez et al., 2020 https://doi.org/10.1186/s11689-020-09328-z).

 In addition, the lab has implemented a cellular model of Rett syndrome that replicates several aspects of the disease, including shortened and less-branched dendrites, cell soma shrinkage, loss of spines and synapses (Baj et al., 2014 https://doi.org/10.3389/fncel.2014.00018, Nerli et al. 2020 https://doi.org/10.1038/s41598-020-59268-w). Using a miniaturized version of this assay in 96 multiwell plate format, and automated microscopy analysis, the lab has carried out a phenotypic drug-screening of a library of FDA-approved drugs leading to the identification of several candidate compounds able to fully recover the pathological phenotype observed in vitro (Roggero et al. unpublished).