Mechanistic Insights Underlying LZTR1-Related Schwannomatosis - SUMMARY Schwannomatosis is a rare neurogenetic disorder characterized by the development of Schwann cell tumors, known as schwannomas, which grow along different nerves, causing significant morbidity and pain. There are at least three different types of this condition, based on their genetic etiology and clinical presentation: NF2, LZTR1, and SMARCB1-related schwannomatosis. Recently, LZTR1-related schwannomatosis has emerged as a novel form of this group of disorders, caused by a complex 3-step, 4-hit genetic mechanism involving the concomitant bi-allelic loss of LZTR1 and NF2 somatically. The treatment for LZTR1-related schwannomatosis has been limited to neurosurgery and/or radiotherapy to remove the schwannomas. However, the efficacy of these procedures is hampered by tumor numbers, location, recurrence, and the appearance of new lesions. Pharmacological strategies to treat or prevent schwannoma formation have not yet been discovered, likely due to the lack of preclinical models that allow for the study of the pathophysiology of the disorder and can be used to test experimental therapies. Our laboratory and others have discovered that LZTR1 is a substrate adaptor for the E3 RING Ubiquitin ligase Cullin-3, which binds and promotes the ubiquitination and degradation of the RAS GTPase proteins RIT1 and MRAS. Bi-allelic inactivation of LZTR1 leads to the accumulation of RIT1 and MRAS, promoting the activation of downstream signaling pathways such as RAS/MAPK. In this application, we propose to study the molecular and cellular mechanisms underlying LZTR1-related schwannomatosis by developing a series of cellular and animal models of this rare disease and identifying potential therapeutic strategies. Specifically, in aim 1 we will study the consequences of LZTR1 loss in Schwann cells and progenitors using human and rodent cellular models. We will assess changes in signaling, gene expression, and cellular functions, including their ability to myelinate axons. In aim 2, we will analyze the mechanisms underlying the epistatic genetic interaction between LZTR1 and NF2 loss in Schwann cells. We will conduct single-cell studies to assess changes in the cellular landscape caused by this genetic interaction and determine the schwannoma-forming capacity of LZTR1/NF2 double knockout Schwann cells. Finally, in aim 3 we will assess potential therapeutic interventions for LZTR1-related schwannomatosis by leveraging novel preclinical models of this disorder. Overall, our application aims to bridge a critical knowledge gap in the field by discovering the molecular mechanisms underlying LZTR1-related schwannomatosis, developing unique preclinical models, and testing novel therapeutic interventions in such models. In the long term, our work will provide the experimental groundwork to initiate clinical trials aimed at treating and preventing schwannomas in patients suffering from this condition.
