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Instytut Biologii Doświadczalnej im. Marcelego Nenckiego PAN ; Międzynarodowy Instytut Biologii Molekularnej i Komórkowej
Contributor: Publisher:Instytut Biologii Doświadczalnej im. Marcelego Nenckiego PAN
Place of publishing: Date issued/created: Description:220 pages : illustrations ; 30 cm ; Bibliography ; Summary in English
Degree name: Degree discipline : Degree grantor:Nencki Institute of Experimental Biology PAS ; degree obtained: 2025
Type of object: Subject and Keywords:KIF ; Kinesin ; Molecular transport ; mTOR ; Neurons ; TSC
Abstract:
Tuberous sclerosis complex (TSC) is a rare, genetic disorder characterized by the development of numerous benign tumors in various organs, including the brain. Neurological symptoms include drugresistant seizures, intellectual disability, and autism spectrum disorder. The genetic basis of the disease lies in mutations in the TSC1 or TSC2 genes, which encode a protein complex that normally inhibits the mTOR kinase, resulting in its excessive activation. At the level of a single neuron, this manifests in a significant increase in cell size and uncontrolled growth of the dendritic tree. Since the use of classical mTOR inhibitors such as rapamycin in treating the disease, is associated with numerous side effects, it is desirable to develop new therapeutic targets, which could be aided by a better understanding of the processes occurring in affected cells. One such process, which is poorly understood in the context of mTOR hyperactivation, is microtubule transport. In neurons, due to their unique structure with long dendrites and axons, this process occurs over exceptionally long distances. This transport is carried out by two groups of proteins – dynein and kinesins. Previous research conducted in the Laboratory of Molecular and Cellular Neurobiology revealed some connections between mTOR and the regulation of dynein-mediated transport, but no such interactions are known for kinesins. Therefore, the main goal of this study was to determine whether any of the proteins belonging to the kinesin family, are necessary for the observed excessive neuronal growth in the TSC model, resulting from mTOR hyperactivation. Through screening studies, it was shown that KIF11, KIF12, KIF13A, KIF13B, KIF14, KIF15, KIF16B, KIF18A, KIF18B, KIF19, KIF1A, KIF1B, KIF20A, KIF21A, KIF21B, KIF22, KIF23, KIF24, KIF26A, KIF26B, KIF27, KIF2A, KIF2B, KIF2C, KIF3A, KIF3B, KIF3C, KIF4A, KIF5A, KIF5C, KIF6, KIF7, KIFC1, KIFC2, and KIFC3 may be necessary for the excessive neuronal growth caused by activation of the mTOR pathway through phosphoinositide 3-kinase (PI3K), while KIF3A, KIF3C, KIF21B, and KIF26B may be involved in excessive neuronal growth resulting from TSC2 silencing. In the second part of the study, an attempt was made to identify potential mechanisms by which the functions of kinesins are crucial for the changes observed in the context of excessive mTOR activation, both in neuronal cells and in rat fibroblast cell lines. The experiments demonstrated some involvement of KIF3A and KIF3C in the regulation of the formation and development of primary cilia, which is disrupted in the TSC model, although the exact nature of this interaction remains unclear.
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Digitizing institution:Nencki Institute of Experimental Biology of the Polish Academy of Sciences
Original in:Library of the Nencki Institute of Experimental Biology PAS
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