Macrophages protect against sensory axon degeneration in diabetic neuropathy
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA1075431 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR27940560.fastq.gz | Fastqsanger.gz | |||
| SRR27940561.fastq.gz | Fastqsanger.gz | |||
| SRR27940562.fastq.gz | Fastqsanger.gz | |||
| SRR27940563.fastq.gz | Fastqsanger.gz | |||
| SRR27940564.fastq.gz | Fastqsanger.gz |
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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.
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Project description:Axon degeneration sculpts precise patterns of connectivity in the developing nervous system and is an early pathological hallmark of several adult-onset neurodegenerative disorders. Substantial progress has been made in identifying effector mechanisms that drive axon fragmentation, but far less is known about the upstream signaling pathways that initiate this process. Here we describe a role for the newly discovered axonal Membrane-associated Periodic Skeleton (MPS) –a quasi-1D periodic ultrastructure composed of actin, spectrin and associated molecules– during sensory axon degeneration. We find that trophic deprivation (TD) of sensory axons causes a rapid breakdown in the periodicity of the MPS in distal axons. These structural changes occur prior to and independently of caspase-driven axon fragmentation. We further show that acute actin destabilization to break down the MPS can initiate TD-related retrograde signaling. Actin stabilization prevents MPS breakdown during TD and blocks this signal. Moreover, deletion of βII-spectrin (Sptbn1), an obligate component of the MPS, suppresses this retrograde signaling and protects axons against degeneration. Together our data suggest that ultrastructural plasticity of the MPS underlies the earliest steps of axon degeneration.
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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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