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IMPDH2 filaments protect from neurodegeneration in AMPD2 deficiency

ABSTRACT: IMPDH2 filaments protect from neurodegeneration in AMPD2 deficiency

PROVIDER: PRJNA1063698 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR27494642_1.fastq.gz	Fastqsanger.gz
	SRR27494642_2.fastq.gz	Fastqsanger.gz
	SRR27494643_1.fastq.gz	Fastqsanger.gz
	SRR27494643_2.fastq.gz	Fastqsanger.gz
	SRR27494644_1.fastq.gz	Fastqsanger.gz

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IMPDH2 filaments protect from neurodegeneration in AMPD2 deficiency

Project description: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.

2024-01-16 | GSE253045 | GEO

IMPDH2 filaments protect from neurodegeneration in AMPD2 deficiency

Project description: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 mouse models of a childhood neurodegenerative disorder caused by AMPD2 deficiency to study cellular and molecular mechanisms that lead to selective neuronal vulnerability to purine metabolism imbalance. We show that AMPD2 mouse models exhibit predominant degeneration of the hippocampal dentate gyrus, despite a general reduction of brain GTP levels. Neurodegeneration-resistant regions accumulate micron-sized filaments of IMPDH2, the rate limiting enzyme in GTP synthesis, while these filaments are barely detectable in the hippocampal dentate gyrus. Furthermore, we show that IMPDH2 filament disassembly reduces GTP levels and impairs growth of neural progenitor cells derived from individuals with human AMPD2 deficiency. Together, our findings suggest that IMPDH2 polymerization prevents detrimental GTP deprivation, opening the possibility of exploring the induction of IMPDH2 assembly as a therapy for neurodegeneration.

| S-SCDT-10_1038-S44319-024-00218-2 | biostudies-other

Nuclear IMPDH2 controls the DNA damage response by modulating PARP1 activity

Project description:Nuclear metabolism and DNA damage response are intertwined processes, but the precise molecular connections remain elusive. Here, we delve into this crosstalk using as a model triple-negative breast cancer (TNBC), a subtype often prone to DNA damage accumulation. We reveal that the de novo purine synthesis enzyme Inosine monophosphate dehydrogenase 2 (IMPDH2) is enriched on chromatin in TNBC when compared to other subtypes. IMPDH2 chromatin localization is DNA damage dependent and IMPDH2 repression leads to DNA damage accumulation. On chromatin, IMPDH2 interacts and modulates Poly [ADP-ribose] polymerase 1 (PARP1) activity by controlling nuclear availability of nicotinamide adenine dinucleotide (NAD+) -a shared metabolic cofactor- to fine-tune the DNA damage response. However, when IMPDH2 is restricted to the nucleus, it depletes nuclear NAD+, leading to PARP1 cleavage and cell death. Our study identifies a non-canonical nuclear role for IMPDH2 that act as convergence point of nuclear metabolism and DNA damage response. # Contributed equally *Corresponding authors: sara.sdelci@crg.eu; marta.garciacao@crg.eu

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Altered lipid homeostasis underlies selective neurodegeneration in SNX14 deficiency.

Project description:Altered lipid homeostasis underlies selective neurodegeneration in SNX14 deficiency.

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Effect of deletion of Impdh2 on gene expression in the forlimbs from E12.5 embryos and osteoclasts (OCs)

Project description:Many factors are essential for skeletal development and homeostaisis. Here we report that inosine monophosphate dehydrogenase type II (Impdh2) is a key positive regulator for limb development and bone resorption. Deletion of Impdh2 in limb mesenchymal progenitors impaired the differentiation of mesenchymal cells into chondrocyte. Meanwhile, deletion of Impdh2 in osteoclast precursors results in mice an osteopetrotic phenotype via suppressing osteoclast differentiation. Our results reveal a previously unrecognized role of Impdh2 on skeletal development and homeostasis.

2023-11-30 | GSE244054 | GEO

Nuclear IMPDH2 controls the DNA damage response by modulating PARP1 activity

Project description:Recent studies have highlighted the critical role of metabolism in the response to DNA damage. However, the precise metabolic interactions that are set in motion to tune this fundamental process remain largely unknown. In this study, we investigated the role of nuclear metabolism in the DNA damage response using triple-negative breast cancer as a model. By comparing the chromatin-associated proteome of different breast cancer subtypes, we observed that the purine synthesis enzyme Inosine monophosphate dehydrogenase 2 (IMPDH2) is enriched in the chromatin of triple-negative breast cancer cells, which are often prone to DNA damage accumulation. Downregulation, depletion, or inhibition of IMPDH2 leads to accumulation of DNA damage. IMPDH2 chromatin localization is DNA damage dose dependent and happens at a late stage of the DNA damage repair. On chromatin, IMPDH2 interacts with PARP1. The enzymatic function of IMPDH2, which consumes NAD+, modulates PARP1 activity, thus mediating a pondered DNA damage response. However, forcing the nuclear localization of exogenous IMPDH2 provokes a dramatic NAD+ depletion that results in PARP1 cleavage and consequent cytoplasmic translocation, which mediates apoptosis. Our study identifies a moonlighting role for IMPDH2 in the control of nuclear ATP and NAD+ level, which fine-tune the activation of PARP1 and regulates the DNA damage response.

2024-11-28 | PXD043522 | Pride

Inosine Monophosphate Dehydrogenase 2 (IMPDH2) Modulates Response to Therapy and Chemo-Resistance in Triple Negative Breast Cancer

Project description:Triple negative breast cancer (TNBC) is one of the deadliest subtypes of breast cancer, whose high frequency of relapse is often due to occurrence of resistance to chemotherapy. Here, we identify inosine monophosphate dehydrogenase 2 (IMPDH2) as a contributor to doxorubicin resistance in different TNBC models. Analysis of public dataset reveals elevated IMPDH2 expression to correlate with worse overall TNBC prognosis in the clinic, including lower recurrence-free survival post adjuvant/neoadjuvant therapy. Importantly, genetic depletion or pharmacological inhibition of IMPDH2 leads to reduction of pro-tumorigenic phenotypes in multiple doxorubicin-resistant TNBC models, both in vitro and in vivo. Overall, we propose IMPDH2 as a novel vulnerability that could be leveraged therapeutically to suppress and/or prevent the growth of chemoresistant lesions.

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Altered lipid homeostasis underlies selective neurodegeneration in SNX14 deficiency [1 yr]

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