Mewborne, Quinlan T.

Abstract NF2-related schwannomatosis is a genetic condition characterized by mutation in the NF2 gene resulting in tumor formation throughout the nervous system. The most common tumors in these patients include bilateral vestibular schwannomas and multiple meningiomas which, despite their benign classification, lead to significant neurologic deficits including hearing loss, ataxia, hydrocephalus, and brainstem compression. Loss of NF2, which encodes the protein Merlin, is also the most common mutation in spontaneous meningiomas and schwannomas. Current treatment consists of resection followed by radiation for more aggressive tumors. Unfortunately, these treatments are not curative and are associated with significant risk due to tumor location, involvement of neurovasculature, cognitive impairment, and radiation-induced tumor induction. Therefore, identifying additional therapeutics for these patients is critical. Molecular profiling across large cohorts of sporadic meningiomas have identified molecular signatures associated with NF2 mutation, indicating upregulation of Wnt5a/b and the alternative Wnt5a/b-YAP/TAZ signaling pathway. In NF2 knock-out human arachnoid and Schwann cells, we find a significant upregulation of YAP in NF2-null lines compared to controls. Additionally, when stimulated with Wnt5a/b, controls upregulate both beta catenin (canonical Wnt) and YAP (alternative Wnt). However, in NF2-null lines only YAP is increased, indicating a preference for the alternative pathway in the absence of canonical Wnt signaling. In primary NF2-mutant meningioma lines, targeting this pathway via blocking Wnt secretion with the inhibitor LGK974 or YAP signaling with verteporfin, which is FDA approved, results in decreased cell viability and proliferation in vitro. These results indicate activation of the Wnt5a/b-YAP/TAZ alternative signaling pathway in NF2-mutant meningeal and Schwann cells, and a potential therapeutic effect of blocking this pathway in NF2-mutant meningiomas with a previously-FDA approved inhibitor. Additional research is needed on the receptors and molecular mediators playing a role in this pathway and how these drugs may have therapeutic benefits in vivo

Arginine-rich dipeptide repeat proteins (R-DPRs), abnormal translational products of a GGGGCC hexanucleotide repeat expansion in C9ORF72 , play a critical role in C9ORF72 -related amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD), the most common genetic form of the disorders (c9ALS/FTD). R-DPRs form liquid condensates in vitro, induce stress granule formation in cultured cells, aggregate, and sometimes coaggregate with TDP-43 in postmortem tissue from patients with c9ALS/FTD. However, how these processes are regulated is unclear. Here, we show that loss of poly(ADP-ribose) (PAR) suppresses neurodegeneration in c9ALS/FTD fly models and neurons differentiated from patient-derived induced pluripotent stem cells. Mechanistically, PAR induces R-DPR condensation and promotes R-DPR–induced stress granule formation and TDP-43 aggregation. Moreover, PAR associates with insoluble R-DPR and TDP-43 in postmortem tissue from patients. These findings identified PAR as a promoter of R-DPR toxicity and thus a potential target for treating c9ALS/FTD.