Neuroinflammatory signatures in mouse models of EPG5-associated neurodegenerative disorders
Presenter Status
Graduate Student
Abstract Type
Translational Research
Primary Mentor or Principal Investigator
Jay L. Vivian
Presentation Type
Poster
Start Date
20-5-2026 11:00 AM
End Date
20-5-2026 12:00 PM
Abstract Text
Background:
EPG5 encodes a critical component of the intracellular machinery which couples the autophagosome to the lysosome for degradation. Recessive pathogenic variants in EPG5 cause a spectrum of neurodegenerative disorders (EPG5-NDs). In children, loss of function variants manifest as Vici Syndrome (VS), which presents as severe developmental delay, seizures, hypotonia, and progressive loss of motor function, with a median survival of only 42 months. Less severe biallelic variants manifest as Parkinson's Disease (PD)-like phenotypes, with early adult onset. Therapies do not exist for EPG5-NDs, in part due to lack of preclinical models and a limited understanding of disease etiology.
Objectives/Goal:
Studies of disease etiology and progression of EPG5-NDs, will have an impact on therapeutic development; therapies are desperately needed to enhance and extend the quality of life of these children. Our primary goals of this study are to develop validated animal models that recapitulate the relevant molecular, cellular, and whole animal aspects of the disease to understand disease etiology and to assess efficacy and safety of candidate therapies.
Methods/Design:
Our team has engineered three novel mouse models of Vici Syndrome using CRISPR-based genome editing to recapitulate two clinically identified pathogenic variants of EPG5, in addition to a knockout allele. Furthermore, a conditional knockout model is currently under development, as well as a strain with an allele that recapitulates a familial early onset parkinsonism pathogenic variant.
Results:
All models exhibited neurological deficits to varying degrees, with progressive loss of motor function and coordination. Whole transcriptomic gene expression analysis uncovered important molecular phenotypes that correlate with the whole animal neurological dysfunction. Pathway analysis identified a substantial neuroinflammatory phenotype, suggesting inflammation may be an important driver of EPG5-ND disease progression. These gene expression deficits were progressively more severe with age. Importantly, a strong glial response was observed in these models, including an expansion of astrocytes and microglia. Tissue analyses confirm systemic gliosis throughout the CNS. Molecular characterization suggested a novel microglial response reminiscent of molecular signatures associated with other mouse models of adult-onset neurodegenerative disorders. Ongoing CNS tissue analyses, including histology and spatial transcriptomics, will further validate our findings.
Conclusions:
These animal models have uncovered novel cellular and molecular phenotypes associated with defective autophagy which may be an underlying basis of the clinical phenotypes of EPG5-NDs. Future studies will leverage these models to dissect the cell-intrinsic requirement for autophagy in driving the neurological phenotypes and the role of neuroinflammation in disease progression. These models also provide critical in vivo platforms for assessment of efficacy of potential therapies identified in our ongoing drug discovery efforts.
Neuroinflammatory signatures in mouse models of EPG5-associated neurodegenerative disorders
Background:
EPG5 encodes a critical component of the intracellular machinery which couples the autophagosome to the lysosome for degradation. Recessive pathogenic variants in EPG5 cause a spectrum of neurodegenerative disorders (EPG5-NDs). In children, loss of function variants manifest as Vici Syndrome (VS), which presents as severe developmental delay, seizures, hypotonia, and progressive loss of motor function, with a median survival of only 42 months. Less severe biallelic variants manifest as Parkinson's Disease (PD)-like phenotypes, with early adult onset. Therapies do not exist for EPG5-NDs, in part due to lack of preclinical models and a limited understanding of disease etiology.
Objectives/Goal:
Studies of disease etiology and progression of EPG5-NDs, will have an impact on therapeutic development; therapies are desperately needed to enhance and extend the quality of life of these children. Our primary goals of this study are to develop validated animal models that recapitulate the relevant molecular, cellular, and whole animal aspects of the disease to understand disease etiology and to assess efficacy and safety of candidate therapies.
Methods/Design:
Our team has engineered three novel mouse models of Vici Syndrome using CRISPR-based genome editing to recapitulate two clinically identified pathogenic variants of EPG5, in addition to a knockout allele. Furthermore, a conditional knockout model is currently under development, as well as a strain with an allele that recapitulates a familial early onset parkinsonism pathogenic variant.
Results:
All models exhibited neurological deficits to varying degrees, with progressive loss of motor function and coordination. Whole transcriptomic gene expression analysis uncovered important molecular phenotypes that correlate with the whole animal neurological dysfunction. Pathway analysis identified a substantial neuroinflammatory phenotype, suggesting inflammation may be an important driver of EPG5-ND disease progression. These gene expression deficits were progressively more severe with age. Importantly, a strong glial response was observed in these models, including an expansion of astrocytes and microglia. Tissue analyses confirm systemic gliosis throughout the CNS. Molecular characterization suggested a novel microglial response reminiscent of molecular signatures associated with other mouse models of adult-onset neurodegenerative disorders. Ongoing CNS tissue analyses, including histology and spatial transcriptomics, will further validate our findings.
Conclusions:
These animal models have uncovered novel cellular and molecular phenotypes associated with defective autophagy which may be an underlying basis of the clinical phenotypes of EPG5-NDs. Future studies will leverage these models to dissect the cell-intrinsic requirement for autophagy in driving the neurological phenotypes and the role of neuroinflammation in disease progression. These models also provide critical in vivo platforms for assessment of efficacy of potential therapies identified in our ongoing drug discovery efforts.
Comments
Restricted to Title/Author List/Abstract only as requested by primary author
Poster Board Number: 29