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

## TL;DR

Researchers created new mouse models of Vici syndrome to study how genetic mutations cause neurological decline and found that brain inflammation plays a key role.

## Contribution

The study introduces novel Epg5 mutant mouse models that mimic patient-derived pathogenic variants and reveals a role for neuroinflammation in Vici syndrome.

## Key findings

- Epg5 mutant mice show progressive neurological deficits and perinatal lethality.
- Transcriptomic analysis reveals robust neuroinflammatory signatures in the central nervous system.
- The findings suggest that neuroglial activation contributes to the pathogenesis 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.

Vici syndrome is a rare genetic disorder in children affecting multiple body systems, including the brain and heart. It often leads to developmental delays and other severe health issues. Researchers have struggled to understand this condition owing to its rarity and lack of effective models for study, limiting treatment options. Here, researchers aimed to fill this gap by creating new mouse models that mimic the genetic mutations found in patients with Vici syndrome. They used a technique called CRISPR gene editing to introduce specific mutations into mice. These mice showed early signs of neurological problems, similar to those seen in human patients. The study found that these mutations led to increased inflammation in the brain, which is important for brain health. The findings suggest that inflammation may play a key role in the progression of Vici syndrome.

This summary was initially drafted using artificial intelligence, then revised and fact-checked by the author.