A C. Elegans Model of Fanconi Anemia Neurological Syndrome

PROJECT SUMMARY Fanconi anemia (FA) is a genetic disease characterized by increased risk for bone marrow failure and cancer, with few therapeutic options. In recent years, central nervous system defects have become increasingly observed among FA patients. These include early-onset progressive and irreversible neurological decline. These neurological manifestations have been collectively coined Fanconi Anemia Neurological Syndrome or FANS. Importantly, the molecular etiology of FANS is unknown. Recent omics approaches from our laboratory have uncovered mechanistic links between the FA proteins and the nervous system. Using ChIP-seq, we have discovered that the FANCD2 protein binds to numerous large neural genes, including genes that function in neuronal differentiation, migration, and cell-cell adhesion. RNA-seq analysis has also revealed differential expression of many of these genes in FA patient cells. Importantly, many FANCD2 target genes are genetically linked to neuropsychiatric and neurodevelopmental disorders such as autism spectrum disorder (ASD), schizophrenia, and intellectual disability, as well as Alzheimer’s disease and related dementias (AD/RD). Our preliminary findings suggest a role for the FA pathway in the maintenance of genome stability during neural stem and progenitor cell expansion during neurogenesis. Defects in this process are highly likely to lead to nervous system dysfunction across the lifespan, characteristic of FANS. In this R15 AREA application, we will use the model nematode Caenorhabditis elegans to study the molecular etiology of FANS. Three specific aims are proposed; In aim 1, we will examine the roles of orthologs of several FA proteins in nervous system function across the lifespan using behavioral paradigms linked to neuronal subclasses associated with human neurological disorders. In aim 2, we will generate FA animals expressing GFP-labeled cholinergic, dopaminergic, GABAergic, and glutamatergic neurons, and neurons will be analyzed for numerical and structural defects using confocal microscopy. We will also perform neuron-specific RNA-seq analysis to determine which genes/pathways are differentially expressed between wild-type and FA transgenic animals. In aim 3, to gain insights into the mechanisms by which the FA pathway maintains genome stability during neurogenesis, we will use PacBio long-read sequencing to examine the role of the FA pathway in the suppression of genomic structural variation. For FANS and AD/RD, there is an urgent need to identify molecular targets to prevent, delay, and/or ameliorate clinical manifestations. Our studies could lead to the identification of new molecular targets linked to FANS and AD/RD, and open new avenues of potential therapeutic intervention.