Twórca instytucjonalny:

Instytut Biologii Doświadczalnej im. Marcelego Nenckiego PAN ; Międzynarodowy Instytut Biologii Molekularnej i Komórkowej

Współtwórca:

Jaworski, Jacek : Supervisor ; Zmorzyńska, Justyna : Assistant supervisor

Wydawca:

Międzynarodowy Instytut Biologii Molekularnej i Komórkowej

Miejsce wydania:

Warszawa

Opis:

163 pages : illustrations ; 30 cm ; Bibliography ; Summary in English

Instytucja nadająca tytuł:

Instytut Biologii Doświadczalnej im. Marcelego Nenckiego PAN

Typ obiektu:

Thesis

Abstrakt:

Tuberous sclerosis complex (TSC) is a rare genetic disease characterized by a highly variable clinical picture. Numerous cellular and tissue dysplasias are observed in this disease in multiple organs, including the central nervous system. Some of these characteristic neuropathological changes can already be detected during fetal development. Patients with TSC also exhibit neurological symptoms such as epilepsy which often develop during the first two years of life. Equally important but often overlooked manifestations of this disease are TSC-associated neuropsychiatric disorders (TANDs). The TSC pathogenesis results mainly from hyperactivity of the mTORC1 pathway caused by loss-of-function mutations in TSC1 or TSC2 genes. This work aims to characterize neuroanatomical, behavioral, and molecular changes in the zebrafish model of TSC tsc2vu242/vu242, and investigate the effects of selected drugs on the observed phenotypes. In the first part of this thesis, I showed that homozygous mutants exhibit alterations in locomotor activity, associated with hyperactivity of the mTORC1 pathway and seizures. Furthermore, based on in-depth behavioral analysis, it was found that tsc2vu242/vu242 larvae exhibit phenotypes similar to TANDs, such as increased anxiety and cognitive impairment. The quantitative analysis of cortisol levels further supported the hypothesis of increased anxiety in this model. The second part of the study examined pathologies of the selected neuronal circuits in the brain of tsc2vu242/vu242 mutants identifying disturbances in the morphology of the anterior commissure and the directed axonal growth leading to impaired axon fasciculation. These abnormalities coexisted with altered mRNA levels of genes of the Dock-Elmo-Rac1 pathway, which is involved e.g., in axon elongation, indicating a molecular basis for the observed neuroanatomical changes. Molecular analysis also revealed the probable disturbance of inhibitory neurotransmission, which is one of the reasons for the initiation of epileptic seizures and the development of intellectual disability in the TSC patients. Furthermore, the effects of the TSC clinical drugs, rapamycin and vigabatrin, on selected neurological and behavioral changes were examined. Rapamycin was effective in rescuing both behavioral phenotypes and neuroanatomical abnormalities in the anterior commissure of the brain in the tsc2vu242/vu242 mutants. Vigabatrin reversed phenotypes reflecting seizures but did not improve the parameters associated with increased anxiety in the tsc2vu242/vu242 mutants. In addition, a novel compound, ANA-12, was identified as a potential treatment for TSC-related symptoms, as it had a positive effect on some aspects of anxiety-related behavior and improved anterior commissure morphology.

Szczegółowy typ zasobu:

PhD Dissertations

Identyfikator zasobu:

oai:rcin.org.pl:234664

Źródło:

IBD PAN, call no. 19933

Język:

pol

Język streszczenia:

eng

Digitalizacja:

Nencki Institute of Experimental Biology of the Polish Academy of Sciences

Lokalizacja oryginału:

Library of the Nencki Institute of Experimental Biology PAS

Dostęp:

Open