Neurofibromatosis type 1 (NF1) is amongst the most common monogenic neurodevelopmental disorder, affecting ∼1 in 2800 live births worldwide. While most of the research has focused on NF1 as a tumor predisposition syndrome, with a third of affected individuals developing central and peripheral nervous system malignancies, the vast majority of children and adults with NF1 present with neurodevelopmental, cognitive and behavioral anomalies. Despite their high prevalence, the extreme heterogeneity in clinical manifestation has hindered systematic efforts to define their molecular underpinnings and, in turn, to develop effective targeted therapies.The elucidation of specific molecular networks governing NF1 neurocognitive pathology is further hindered by the paucity of preclinical platforms faithfully modeling these phenotypes. Even in cases where the specific molecular pathways are delineated, such as RAS-dependent memory defects, and cAMP- and dopamine-mediated learning and cognitive functions, therapeutic advances have not translated successfully to patients. Agents that corrected phenotypes in genetically engineered murine models have largely failed in clinical trials, as exemplified by studies of lovastatin and related compounds. This translational gap is likely to reflect multiple factors, including species-specific neurobiology, genomic background and the diversity of germline NF1 mutations modeled across experimental models.In an effort to identify actionable molecular targets and accelerate therapeutic efforts through drug repurposing, Miller, Halloran and colleagues leveraged nf1 mutant zebrafish with known behavioral deficits in habituation. The authors first employed RNA sequencing to analyze disease-associated gene expression changes and, in parallel, conducted a small-molecule drug screen to identify agents able to reverse habituation deficits. By combining these complementary approaches, the authors discovered that the chemokine receptor Cxcr4 is a key regulator of the observed behavioral deficits. Mechanistically, the nf1-dependent upregulation of cxcr4 gene expression was associated with cAMP–PKA pathway dysregulation and impaired habituation. This was reversed following pharmacologic inhibition of cxcr4 with plerixafor, a drug used to expand bone marrow stem cell circulation in the blood stream for collection prior to transplantation.This study reiterates the importance of known molecular targets deregulated in NF1 (e.g. CXCR4, cAMP, PKA) beyond tumorigenesis, which demonstrates the interconnectivity of these molecular signaling pathways, reconciling previous studies in mice and Drosophila. Importantly from a translational medicine lens, this study highlights the potential of repurposing drugs for the treatment of NF1-associated neurocognitive dysfunction.
Corina Anastasaki (Sun,) studied this question.