Current Approaches and Future Directions for the Treatment of mTORopathies

Abstract

The mechanistic target of rapamycin (mTOR) is a kinase at the center of an evolutionarily conserved signaling pathway that orchestrates cell growth and metabolism. mTOR responds to an array of intra- and extracellular stimuli and in turn controls multiple cellular anabolic and catabolic processes. Aberrant mTOR activity is associated with numerous diseases, with particularly profound impact on the nervous system. mTOR is found in two protein complexes, mTOR complex 1 (mTORC1) and 2 (mTORC2), which are governed by different upstream regulators and have distinct cellular actions. Mutations in genes encoding for mTOR regulators result in a collection of neurodevelopmental disorders known as mTORopathies. While these disorders can affect multiple organs, neuropsychiatric conditions such as epilepsy, intellectual disability, and autism spectrum disorder have a major impact on quality of life. The neuropsychiatric aspects of mTORopathies have been particularly challenging to treat in a clinical setting. Current therapeutic approaches center on rapamycin and its analogs, drugs that are administered systemically to inhibit mTOR activity. While these drugs show some clinical efficacy, adverse side effects, incomplete suppression of mTOR targets, and lack of specificity for mTORC1 or mTORC2 may limit their utility. An increased understanding of the neurobiology of mTOR and the underlying molecular, cellular, and circuit mechanisms of mTOR-related disorders will facilitate the development of improved therapeutics. Animal models of mTORopathies have helped unravel the consequences of mTOR pathway mutations in specific brain cell types and developmental stages, revealing an array of disease-related phenotypes. In this review, we discuss current progress and potential future directions for the therapeutic treatment of mTORopathies with a focus on findings from genetic mouse models.

Dysregulation of mTOR Signaling after Brain Ischemia

“…Mammalian/mechanistic target of rapamycin (mTOR) is a 289 kDa serine–threonine kinase and a key element of two mTOR complexes called mTORC1 and mTORC2 (mTORCs) [ 1 , 2 , 3 , 4 ]. Furthermore, mTOR is highly conserved and is the center of multiples signaling pathways and coordinates important cellular processes such as cell growth and metabolism [ 5 ]. Although mTOR is ubiquitously expressed, it is especially abundant in the brain [ 6 ].…”

Modeling Somatic Mutations Associated With Neurodevelopmental Disorders in Human Brain Organoids

“…In addition to “mTORopathies”, which are associated with cortical malformations and epilepsy (Karalis and Bateup, 2021 ), brain somatic mutations have been identified in tissue from individuals with a variety of disorders including Rett syndrome, neurofibromatosis type 1, neuronal migration disorders, epileptic encephalopathies, ASD, intellectual disability, schizophrenia, and neurodegenerative diseases (Muotri et al, 2010 ; Garcia-Linares et al, 2011 ; D’gama and Walsh, 2018 ; Park et al, 2019 ; Kim et al, 2021 ; Rodin et al, 2021 ). In particular, several recent studies have shown that brain somatic mutations account for approximately 3–5% of ASD cases from the Simons Simplex Collection (Freed and Pevsner, 2016 ; Dou et al, 2017 ; Krupp et al, 2017 ; Lim et al, 2017a ).…”

“…How these mutations alter nervous system development, synaptic connectivity, and neural circuit activity is an ongoing area of research. Mouse models of NDDs harboring mutations in these genes have revealed an array of developmental, cellular, synaptic, and behavioral phenotypes that have provided insight into the basic functions of these genes and how changes in their expression may lead to NDDs (Verma et al, 2019 ; Bozzi and Fagiolini, 2020 ; Karalis and Bateup, 2021 ). In particular, studying these genes in animal models enables an understanding of the impact of mutations across multiple levels from molecules to circuits to behavior.…”

PARVing the Way to Cap Translation for Seizure Control

“…In particular the mTORC1-dependent arm of the pathway has drawn a lot of interest in the epilepsy field because of the availability of mTORC1-inhibiting drugs approved for use in humans, such as everolimus, that reduce seizures in mouse models and have shown some success in ameliorating the seizure phenotype in patients. 2 Not all patients are responders, though, and the molecular and cellular mechanisms that lead to the development of epilepsy when the mTOR pathway is overactive are still not fully understood. In fact, a few recent studies painted a more nuanced picture of mTOR signaling in epilepsy: Chen et al challenged the “mTORC1-centric” view of epilepsy by showing that genetic reduction of the other arm of mTOR signaling, mTORC2, rescues seizure phenotypes in a mouse model of epilepsy, while inhibiting mTORC1 was less effective.…”