Progressive neuroinflammation and deficits in motor function in a mouse model with an Epg5 pathogenic variant of Vici syndrome.

Abstract

Vici syndrome (VS) is a rare pediatric genetic disorder characterized by profound developmental delay, seizures, immune deficits, cardiomyopathy and progressive motor dysfunction. This devastating condition is caused by pathogenic variants in the EPG5 gene, which encodes a regulator of autophagy, leading to the accumulation of toxic intracellular material and widespread cellular dysfunction. Less-severe EPG5 pathogenic variants have recently been linked to rare familial forms of Parkinson's disease, suggesting deficits in EPG5 function drive a range of neurodegenerative disorders. Currently, there are no effective treatments for any disorders associated with pathogenic variants of EPG5. The underlying cellular mechanisms driving the progressive neurological decline in VS remain poorly understood. Previous studies using Epg5 knockout models have demonstrated severe neurological phenotypes; however, these models have not been characterized for molecular and cellular deficits within the central nervous system. Here we report the generation and analysis of novel genetically engineered mice with mutations in Epg5 as models of VS, including a strain harboring a truncating mutation that recapitulates a patient-derived pathogenic variant and a strain with an Epg5 null allele. These novel Epg5 mutant mouse models exhibited partial perinatal lethality. Neurological deficits of surviving were detectable by 6 weeks of age, and worsen over time. Histological analysis revealed widespread expansion of microglia and astrocytes throughout the central nervous system. Transcriptomic profiling of central nervous system tissue revealed robust neuroinflammatory signatures, sharing molecular profiles with disease-associated microglia observed in other models of neurological disease and injury. The analysis of these novel mouse models of VS suggest a critical role for neuroglial activation in the pathogenesis of VS. These novel in vivo models will be an essential platform for preclinical evaluation of therapeutics that target autophagy-related neurodegeneration in congenital disorders of autophagy and EPG5-associated neurodegeneration.