Molecular and Cellular Functions of LZTR1 Mutations in Schwannomatosis
Abstract
Neurofibromatosis type 3, or schwannomatosis, is a genetic disorder that affects 1 in 40,000 people worldwide. It is characterized by the appearance of several benign tumors arising from the peripheral and spinal nerves called schwannomas. Schwannomas develop from Schwann cells, a type of cell that produces myelin, which is a substance that serves as a sheath for the neuronal axons found in nerves. Patients affected by schwannomatosis are diagnosed due to the high number of schwannomas they develop through their life, because in non-affected individuals, this tumor type is rare. The most significant symptom in these patients is chronic pain, which results from the mechanical pressure that schwannomas exert on the surrounding nerves. Schwannomatosis has been linked to familiar and sporadic mutations in a gene termed LZTR1, which encodes for a protein of unknown function. Such mutations inactivate the expression of LZTR1, resulting in the loss of the protein in Schwann cells. We have recently uncovered the main function of this protein and showed that it acts as a molecular scaffold that facilitates degradation of a specific substrate. In normal conditions, LZTR1 interacts with this substrate and promotes its degradation, but in the absence of LZTR1, as a result of mutations, the substrate can no longer be degraded and accumulates in the cells, causing an abnormal cell phenotype. However, the consequences of LZTR1 mutations in the context of schwannomatosis have never been explored. In this proposal, I hypothesize that loss of LZTR1 in Schwann cells results in accumulation of its substrate, a protein that causes uncontrolled proliferation and differentiation into schwannomas. Therefore, I will establish different experimental approaches to test this hypothesis, summarized in three aims. In Aim 1, I will use primary and immortalized Schwann cells that lack LZTR1 to assess the changes in the biology of these cells, including effects on cell growth and proliferation, migration, and differentiation. In Aim 2, I will identify and validate novel substrates of LZTR1 that could be responsible for the phenotype in Schwann cells through different biochemical techniques. In Aim 3, I will develop a novel mouse model of schwannoma that will allow us to test the effect of LZTR1 depletion in schwannoma formation. Altogether, the goal of this proposal is to further understand the role of LZTR1 in the formation of schwannomas, both at the molecular and cellular level. These results will benefit patients suffering from neurofibromatosis type 3, or schwannomatosis, because it will help understand the mechanism of pathogenesis of this incurable disorder. Long term, this important knowledge can be used to identify potential pharmacological treatments that would directly target the genetic source of schwannomas and, ultimately, help these patients.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Mar 10, 2021
- Source ID
- W81XWH2010391
Entities
People
- Pau Castel
Organizations
- United States Army
- University of California, San Francisco