Jacek Jaworski

Lessons from modeling mTORopathies

Abstract

mTORopathies are multiorgan diseases that result from excessive mTOR kinase activity. Common characteristics of mTORopathies include developmental alterations in the cerebral cortex anatomy and the presence of benign brain tumors. Clinically, mTORopathies often present as epilepsy, autism spectrum disorders, and neuropsychiatric disorders. One extensively studied mTORopathy is tuberous sclerosis complex (TSC), which occurs due to the loss of function of TSC1 or TSC2 proteins, both of which inhibit mTOR. mTOR is a kinase whose activity is regulated by trophic factors, energy levels, and amino acid levels within the cell.

In TSC, this regulation is disrupted, leading to deregulation of numerous mTOR-dependent processes such as translation, lipid and nucleotide biosynthesis, autophagy, and transcription. Currently, patients with TSC receive symptomatic treatment, such as the administration of antiepileptic drugs or mTOR inhibitors like rapamycin.

However, there is still a need for new drugs, particularly for TSC-associated neuropsychiatric disorders. In our research, we employ a combination of cellular models (such as in vitro neuron cultures, cells from tumor patients, and induced pluripotent stem cells from patients) and animal models (such as zebrafish and mice) to gain a better understanding of the molecular aspects of neurodevelopment in conditions of mTOR overactivity and to identify new therapeutic targets. This presentation will provide an overview of our team’s research in these two areas.

Biography

Jacek Jaworski is a professor and the Deputy Director for Science at the International Institute of Molecular and Cell Biology in Warsaw, where he leads the Laboratory of Molecular and Cellular Neurobiology. He began his career at the Nencki Institute of Experimental Biology, where he completed his Ph.D. in 2001 under the supervision of Prof. Leszek Kaczmarek. During his time in Prof. Kaczmarek’s lab, his research focused on investigating the role of transcription factors in neuronal cell death.

Subsequently, he joined the Picower Institute for Learning and Memory at MIT, where he studied the molecular mechanisms underlying neuronal development and neuronal structural plasticity. One of his significant contributions during this period was the first demonstration of the involvement of the mTOR kinase in neuronal development. Since joining the IIMCB, Prof. Jaworski’s research team has been dedicated to unraveling the molecular mechanisms responsible for proper neuronal morphology, with a specific emphasis on mTOR-regulated cellular processes.

In his recent work, Prof. Jaworski collaborates with a network of European researchers to investigate how these processes contribute to neurodevelopmental pathologies such as epilepsy and tuberous sclerosis. In addition to his discovery of mTOR’s role in neuronal function, Prof. Jaworski has also made significant contributions in collaboration with Prof. Casper Hoogenraad from Utrecht University. Together, they described for the first time the involvement of microtubule plus-end binding proteins in dendritic tree formation and structural synaptic plasticity in neurons.

The research conducted by Prof. Jaworski and his team has been published in several prestigious peer-reviewed journals, including Neuron, PNAS, EMBO J., and J. Neurosci. This year, he was elected as a member of the European Molecular Biology Organization.