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Series GSE253045 Query DataSets for GSE253045
Status Public on Jan 16, 2024
Title IMPDH2 filaments protect from neurodegeneration in AMPD2 deficiency
Organism Mus musculus
Experiment type Expression profiling by high throughput sequencing
Summary Metabolic dysregulation is one of the most common causes of pediatric neurodegenerative disorders. However, how the disruption of ubiquitous and essential metabolic pathways predominantly affect neural tissue remains unclear. Here we use a mouse model of AMPD2 deficiency to study cellular and molecular mechanisms that lead to selective neuronal vulnerability to purine metabolism imbalance. We show that AMPD deficiency in mice primarily leads to hippocampal dentate gyrus degeneration despite causing a generalized reduction of brain GTP levels. Remarkably, we uncover that neurodegeneration resistant regions of the hippocampus accumulate micron sized filaments of IMPDH2, the rate limiting enzyme in GTP synthesis. In contrast, IMPDH2 filaments are barely detectable in the dentate gyrus, which show a progressively neuroinflammation and neurodegeneration. Furthermore, using a human AMPD2 neural cell culture model, we show that blocking IMPDH2 polymerization with a dominant negative IMPDH2 variant impairs AMPD2 deficient neural progenitor growth. Together, our findings suggest that IMPDH2 polymerization prevents detrimental GTP deprivation caused by AMPD2 deficiency, providing resistance to neurodegeneration. This data opens the possibility of exploring the involvement of IMPDH2 assembly as a therapeutic intervention for neurodegeneration.
Overall design To determine why the hippocampus is more vulnerable to GTP depletion and IMPDH2 assembly in dKO mice, we conducted a mRNA sequencing (RNAseq) analysis of the three brain regions exhibiting different degrees of neurodegeneration and IMPDH2 aggregation: the hippocampus showing neurodegeneration and IMPDH2 filaments, the cerebral cortex with apparently no neurodegeneration and low density of IMPDH2 filaments and the cerebellum with no degeneration or IMPDH2 filaments.
Contributor(s) Flores-Mendez M, Ohl L, Roule T, Zhou Y, A Tintos-Hernandez J, Walsh K, Ortiz-Gonzalez X, Akizu N
Citation(s) 38328116
Submission date Jan 11, 2024
Last update date Feb 15, 2024
Contact name Naiara Akizu
Organization name Children's Hospital of Philadelphia
Department Pathology And Lab Medicine
Lab Akizu Lab
Street address 3501 Civic Center Blvd
City Philadelphia
State/province PA
ZIP/Postal code 19104
Country USA
Platforms (1)
GPL24247 Illumina NovaSeq 6000 (Mus musculus)
Samples (18)
GSM8012885 cerebellum, Ctrl, biol rep 1
GSM8012886 cerebellum, Ctrl, biol rep 2
GSM8012887 cerebellum, Ctrl, biol rep 3
BioProject PRJNA1063698

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