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Animal Models

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Selected Grantee Publications

Impaired Axon Initial Segment Structure and Function in a Model of ARHGEF9 Developmental and Epileptic Encephalopathy

Wang et al., PNAS. 2024.

https://www.pnas.org/doi/10.1073/pnas.2400709121

Researchers developed a mouse model carrying the G55A missense variant identified in ARHGEF9 patients with severe epilepsy and neurodevelopmental phenotypes. Using male Arhgef9G55A mice, this study examined behavioral, molecular, and electrophysiological phenotypes in the Arhgef9G55A model of developmental and epileptic encephalopathies (DEE). Researchers found that the G55A variant causes disruption of inhibitory postsynaptic organization and axon initial segment (AIS) architecture, leading to impairment of both synaptic transmission and action potential generation. The effects of Arhgef9G55A on neuronal function affect both intrinsic and synaptic excitability and preferentially impair AIS. These findings indicate a novel pathological mechanism of DEE and represent a unique example of a neuropathological condition converging from AIS dysfunctions. Supported by ORIP (U54OD020351, U54OD030187, U54OD020351, S10OD026974) and NINDS.

Intrinsic Link Between PGRN and GBA1 D409V Mutation Dosage in Potentiating Gaucher Disease

Lin et al., Human Molecular Genetics. 2024.

https://doi.org/10.1093/hmg/ddae113

Gaucher disease (GD) is an autosomal recessive disorder and one of the most common lysosomal storage diseases. GD is caused by mutations in the GBA1 gene that encodes glucocerebrosidase (GCase), a lysosomal protein involved in glyocolipid metabolism. Progranulin (PGRN, encoded by GRN) is a modifier of GCase, and GRN mutant mice exhibit a GD-like phenotype. The researchers in this study aimed to understand the relationship between GCase and PGRN. They generated a panel of mice with various doses of the GBA1 D409V mutation in the GRN-/- background and characterized the animals’ disease progression using biochemical, pathological, transcriptomic, and neurobehavioral analyses. Homozygous (GRN-/-, GBA1 D409V/D409V) and hemizygous (GRN-/-, GBA1 D409V/null) animals exhibited profound inflammation and neurodegeneration compared to PG96 wild-type mice. Compared to homozygous mice, hemizygous mice showed more profound phenotypes (e.g., earlier onset, increased tissue fibrosis, shorter life span). These findings offer insights into GD pathogenesis and indicate that GD severity is affected by GBA1 D409V dosage and the presence of PGRN. Supported by ORIP (R21OD033660) and NINDS.

Focused Ultrasound–Mediated Brain Genome Editing

Lao et al., PNAS. 2023.

https://www.pnas.org/doi/epdf/10.1073/pnas.2302910120

Gene editing in the brain has been challenging because of the restricted transport imposed by the blood–brain barrier (BBB). In this study, investigators described a safe and effective gene‑editing technique by using focused ultrasound (FUS) to transiently open the BBB for the transport of intravenously delivered CRISPR machinery to the brain in mice. By combining FUS with adeno-associated virus–mediated gene delivery, researchers can achieve more than 25% editing efficiency of particular cell types. This method has the potential to expand toolkit options for CRISPR delivery and opens opportunities for treating diseases of the brain, such as neurodegenerative disorders, with somatic genome editing. Supported by ORIP (U42OD026635) and NINDS.