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Sarm1 knockout prevents type 1 diabetic bone disease in females independent of neuropathy

ABSTRACT: Sarm1 knockout prevents type 1 diabetic bone disease in females independent of neuropathy

PROVIDER: PRJNA1059265 | ENA |

REPOSITORIES: ENA

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Sarm1 knockout prevents type 1 diabetic bone disease in females independent of neuropathy

Project description:Diabetic patients have a high risk of developing skeletal diseases accompanied by diabetic peripheral neuropathy (DPN). In this study, we isolated the role of DPN in skeletal disease with global and conditional knockout models of sterile-α and TIR-motif-containing protein-1 (Sarm1). SARM1, an NADase highly expressed in the nervous system, regulates axon degeneration upon a range of insults, including DPN. Global knockout of Sarm1 prevented DPN, but not skeletal disease, in male mice with type 1 diabetes (T1D). Female wild type mice also developed diabetic bone disease, but without DPN. Unexpectedly, global Sarm1 knockout completely protected female mice from T1D-associated bone suppression and skeletal fragility despite comparable muscle atrophy and hyperglycemia. Global Sarm1 knockout rescued bone health through sustained osteoblast function with abrogation of local oxidative stress responses. This was independent of the neural actions of SARM1, as beneficial effects on bone were lost with neural conditional Sarm1 knockout. This study demonstrates that the onset of skeletal disease occurs rapidly in both male and female mice with T1D completely independent of DPN. In addition, this reveals that clinical SARM1 inhibitors, currently being developed for treatment of neuropathy, may also have benefits for diabetic bone through actions outside of the nervous system.

2024-04-30 | GSE252292 | GEO

Macrophage depletion blocks congenital SARM1-dependent neuropathy

Project description:Axon loss contributes to many common neurodegenerative disorders. In healthy axons, the axon survival factor NMNAT2 inhibits SARM1, the central executioner of programmed axon degeneration. We identified two rare NMNAT2 missense variants in two brothers afflicted with a progressive neuropathy syndrome. The polymorphisms result in amino acid substitutions, V98M and R232Q, which reduce NMNAT2 NAD+-synthetase activity. We generated a mouse model of the human syndrome and found that Nmnat2V98M/Nmnat2R232Q compound-heterozygous CRISPR mice survive to adulthood but develop progressive motor dysfunction, peripheral axon loss, and macrophage infiltration. These disease phenotypes are all SARM1-dependent. Remarkably, macrophage depletion therapy blocks and reverses neuropathic phenotypes in Nmnat2V98M/R232Q mice, identifying a SARM1-dependent neuroimmune mechanism as a key driver of disease pathogenesis. These findings demonstrate that SARM1 induces an inflammatory neuropathy and highlight the potential of immune therapy to treat this rare syndrome and other neurodegenerative conditions associated with NMNAT2 loss and SARM1 activation.

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Macrophage depletion blocks congenital SARM1-dependent neuropathy

Project description:Macrophage depletion blocks congenital SARM1-dependent neuropathy

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Transcription profiling of diabetic neuropathy in dorsal root ganglia from streptozotocin-diabetic male wistar rats over the first 8 weeks of diabetes

Project description:A study of diabetic neuropathy in dorsal root ganglia from streptozotocin-diabetic male wistar rats over the first 8 weeks of diabetes

2006-12-10 | E-MEXP-515 | biostudies-arrayexpress

High-resolution whole-genome DNA methylation revealed unique signatures of painful diabetic neuropathy

Project description:This work describes the DNA methylation signature and identifies genes associated with neuropathic pain in type 2 diabetes mellitus. Genome-wide methylation data for 315 DNA (WB) samples were generated using Illumina Infinium Methylation EPIC v1.0 BeadChip. Four different selection criteria were used to identify promising pain-related genes. The findings revealed significant differences in methylation patterns between painful and painless diabetic neuropathy and identified a set of individual CpG sites of unique candidate genes associated with the painful phenotype. Several of these genes, including GCH1, MYT1L and MED16, have been previously linked to pain-related phenotypes or diabetes. Through pathway enrichment analysis, we demonstrated that specific epigenetic signatures could contribute to the complex phenotype of diabetic neuropathy and cluster analyses highlighted significant epigenetic dissimilarities between painful and painless phenotypes. Our results uncovered epigenetic differences between painful and painless diabetic neuropathy patients and identified targeted genes linked to neuropathic pain through DNA methylation mechanisms. This approach holds promise for investigating other chronic pain conditions, such as secondary chronic pain from cancer treatment, thoracic surgery, and various transplant settings.

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Single-cell transcriptome analysis reveals distinct cell populations in dorsal root ganglia and their potential roles in diabetic peripheral neuropathy

Project description:Diabetic peripheral neuropathy (DPN) is the most common form of neuropathy, and have considerable morbidity, which occurs in approximately 50% of diabetic patients. Here, we performed scRNA-seq technology using 10× Genomics sequencing on DRG tissues isolated from control and DPN rats, to identify the cell type composition of DRG, and to reveal the roles of different cell types in mediating DPN.

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Transcriptional profiling of diabetic peripheral neuropathy patients, diabetic patients, and healthy participants

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Macrophages protect against sensory axon degeneration in diabetic neuropathy

Project description:Diabetic peripheral neuropathy (DPN) is a common complication of diabetes, causing sensory loss and debilitating neuropathic pain1,2. Although the onset and progression of DPN have been linked with dyslipidemia and hyperglycemia3, the contribution of inflammation in the pathogenesis of DPN has not been investigated. Here, we use a High Fat High Fructose Diet (HFHFD) to model DPN and its metabolic syndrome in mice. Diabetic mice develop persistent heat hypoalgesia after three months, but a reduction in epidermal skin innervation only manifests at 6 months. Using single-cell sequencing, we find that CCR2+ macrophages infiltrate the sciatic nerves of diabetic mice well before axonal degeneration is detectable. We show that these infiltrating macrophages share gene expression similarities with nerve crush-induced macrophages4 and express neurodegeneration-associated microglia marker genes5 although there is no axon loss or demyelination yet. Inhibiting this macrophage recruitment in diabetic mice by genetically or pharmacologically blocking CCR2 signaling results in a more severe heat hypoalgesia and accelerated skin denervation. These findings reveal a novel neuroprotective recruitment of macrophages into peripheral nerves of diabetic mice that delays the onset of terminal axonal degeneration, thereby reducing sensory loss. Potentiating and sustaining this early neuroprotective immune response in patients represents, therefore, a potential means to reduce or prevent DPN.

2024-12-03 | GSE255553 | GEO

Macrophages protect against sensory axon degeneration in diabetic neuropathy

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Single cell sequencing datasets of tibial nerves from diabetic neuropathy (DPN) patients and traumatic limb amputation (TLA) patients.

Project description:To understand the cellular diversity and alterations in the pathogenesis of diabetic neuropathy (DPN), weenrolled 4 DPN patients, 3 traumatic limb amputation (TLA) patients at the Department of Orthopedic Surgery of Shanghai Sixth People’s Hospital, Shanghai, China.

2024-12-18 | GSE266026 | GEO

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