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Inhibition of the autophagic protein ULK1 attenuates axonal degeneration in vitro and in vivo and modulates differential splicing

ABSTRACT: Inhibition of the autophagic protein ULK1 attenuates axonal degeneration in vitro and in vivo and modulates differential splicing

PROVIDER: PRJNA509593 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR8313100_1.fastq.gz	Fastqsanger.gz
	SRR8313100_2.fastq.gz	Fastqsanger.gz
	SRR8313095_1.fastq.gz	Fastqsanger.gz
	SRR8313095_2.fastq.gz	Fastqsanger.gz
	SRR8313096_1.fastq.gz	Fastqsanger.gz

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Inhibition of the autophagic protein ULK1 attenuates axonal degeneration in vitro and in vivo and modulates differential splicing

Project description:Several traumatic and neurodegenerative disorders of the CNS show axonal degeneration as a key and early pathological feature. Following a focal axonal lesion, an extended axonal disintegration by acute axonal degeneration (AAD) occurs within several hours. During AAD, activation of autophagic proteins including Unc-51 like autophagy activating kinase 1 (ULK1) has been demonstrated, but its role is incompletely understood. Here, we overexpressed a dominant negative of ULK1 (ULK1.DN) in primary rat cortical neurons in vitro and in the spinal cord (SC) and optic nerve (ON) in vivo. We found a significant inhibitory effect on autophagy in vitro and in vivo. While no effect on cell survival could be observed, ULK1.DN attenuated AAD after axotomy in microfluidic chambers in vitro. Models of SC injury and ON crush in vivo confirmed an attenuation of axonal degeneration by ULK1.DN. In a translational approach, we employed the selective ULK1 inhibitor SBI-0206965 (SBI) and found an attenuation of AAD after ON crush in vivo mediated by a reduction of autophagy by SBI. Quantitative proteomic profiling after ULK1.DN overexpression in vitro revealed a regulation of proteins associated with translation and splicing. A differential exon expression analysis identified the genes kinesin family member 1B (Kif1b), DNA damage inducible transcript 3 (Ddit3) and WD repeat domain 6 (Wdr6) as targets of ULK1.DN and potential mediators of its degeneration-attenuating effect. These findings reveal ULK1 as an important mediator of axonal degeneration and elucidate its function in splicing, defining it as a putative therapeutic target.

2020-09-23 | GSE123687 | GEO

Inhibition of the autophagic protein ULK1 attenuates axonal degeneration in vitro and in vivo and modulates differential splicing

Project description:Several traumatic and neurodegenerative disorders of the CNS show axonal degeneration as a key and early pathological feature. Following a focal axonal lesion, an extended axonal disintegration by acute axonal degeneration (AAD) occurs within several hours. During AAD, activation of autophagic proteins, including Unc-51 like autophagy activating kinase 1 (ULK1), has been shown but its role is incompletely understood. Here, we overexpressed a dominant negative of ULK1 (ULK1.DN) in primary rat cortical neurons in vitro and in the spinal cord (SC) and optic nerve (ON) in vivo. We found a significant inhibitory effect on autophagy in vitro and in vivo. While no effect on cell survival could be observed, ULK1.DN attenuated AAD after axotomy in microfluidic chambers in vitro. Models of SC injury and ON crush in vivo confirmed an attenuation of axonal degeneration by ULK1.DN. In a translational approach, we employed the selective ULK1 inhibitor SBI-0206965 (SBI) and found an attenuation of AAD after ON crush in vivo mediated by a reduction of autophagy by SBI. Quantitative proteomic profiling after ULK1.DN overexpression in vitro revealed a regulation of proteins associated with translation and splicing. A differential exon expression analysis then identified the genes kinesin family member 1B (Kif1b), DNA damage inducible transcript 3 (Ddit3) and WD repeat domain 6 (Wdr6) as targets of ULK1.DN and potential mediators of its degeneration-attenuating effect. These findings reveal ULK1 as an important mediator of axonal degeneration and elucidate its function in splicing, defining it as a putative therapeutic target.

2020-04-30 | PXD011862 | Pride

Inhibition of the autophagic protein ULK1 attenuates axonal degeneration in vitro and in vivo, enhances translation, and modulates splicing.

Project description:Axonal degeneration is a key and early pathological feature in traumatic and neurodegenerative disorders of the CNS. Following a focal lesion to axons, extended axonal disintegration by acute axonal degeneration (AAD) occurs within several hours. During AAD, the accumulation of autophagic proteins including Unc-51 like autophagy activating kinase 1 (ULK1) has been demonstrated, but its role is incompletely understood. Here, we study the effect of ULK1 inhibition in different models of lesion-induced axonal degeneration in vitro and in vivo. Overexpression of a dominant negative of ULK1 (ULK1.DN) in primary rat cortical neurons attenuates axotomy-induced AAD in vitro. Both ULK1.DN and the ULK1 inhibitor SBI-0206965 protect against AAD after rat optic nerve crush in vivo. ULK1.DN additionally attenuates long-term axonal degeneration after rat spinal cord injury in vivo. Mechanistically, ULK1.DN decreases autophagy and leads to an mTOR-mediated increase in translational proteins. Consistently, treatment with SBI-0206965 results in enhanced mTOR activation. ULK1.DN additionally modulates the differential splicing of the degeneration-associated genes Kif1b and Ddit3. These findings uncover ULK1 as an important mediator of axonal degeneration in vitro and in vivo, and elucidate its function in splicing, defining it as a putative therapeutic target.

| S-EPMC7493890 | biostudies-literature

Rac1 impairs retinal axon degeneration via Kif2a in a mouse model of chronic ocular hypertension

Project description:Rac1, a member of the small G protein Rho family, has been implicated in neurodegenerative diseases. However, its role in axon degeneration is not fully understood. Here we found that activation of Rac1 exacerbated axonal transport damage in an experimental glaucoma model. Inhibiting Rac1 activity by genetic or pharmacological methods alleviated the dysfunction of axonal transport and improved the integrity of microtubule by upregulating the expression of β-III tubulin and myelin basic protein. Rac1 interacted with Sirt1, a key molecule of Wallerian degeneration, which regulated the activity of PAK1, a downstream molecule of Rac1. Furthermore, Rac1 modulated Kif motors at the transcriptional level, among which Kif2a, a lysosome-location regulator, was negatively regulated by Rac1. Intravitreal injection of Kif2a siRNA reversed the improvement of Rac1 inhibition-mediated axonal transport through reducing autophagolysosomes. Our results suggest that Rac1/Kif2a accelerates the process of RGC axon degeneration by impairing the autophagic flux in glaucoma, which may be an intriguing therapy target for glaucoma.

2024-12-01 | GSE247696 | GEO

TAX1BP1 deficiency impair initiation of autophagic flow in HK-2 cells through downregulate AMPK-ULK1 pathway

Project description:TAX1BP1 deficiency impair initiation of autophagic flow in HK-2 cells through downregulate AMPK-ULK1 pathway

| PRJNA1083895 | ENA

Myelin insulation as a risk factor for axonal degeneration in autoimmune demyelinating disease

Project description:Axonal degeneration determines the clinical outcome of multiple sclerosis (MS), and is thought to result from exposure of denuded axons to immune-mediated damage. We challenge this view after finding in MS and its mouse models that myelin itself increases the risk of axons to degenerate under inflammatory conditions. We propose a model for demyelinating diseases in which for axons that remain myelinated, and thus shielded from the extracellular milieu, dependence from oligodendroglial support turns fatal in an autoimmune disease environment.

2023-05-02 | GSE222063 | GEO

Central Role of ULK1 in Type I Interferon Signaling

Project description:We provide evidence that the Unc-51-like kinase 1 (ULK1) is phosphorylated and activated during engagement of the Type I IFN receptor. Our studies demonstrate that the function of ULK1 controls expression of key interferon stimulated genes (ISGs) that mediate important biological functions, including anti-viral and antineoplastic responses. Total RNA was isolated from untreated and IFNβ-treated Ulk1/2+/+ and Ulk1/2-/- mouse embryonic fibroblasts (MEFs). Cells were treated for 6 hours with or without mouse IFNβ (2500 IU/ml).

2014-08-26 | E-GEOD-60778 | biostudies-arrayexpress

VAMP7-dependent autophagic secretion allows for axonal resilience in growth restricting conditions.VAMP7-dependent autophagic secretion allows for axonal resilience in growth restricting conditions.

Project description:VAMP7 is involved in autophagy and exocytosis mediating neurite growth, two yet unconnected cellular pathways. Here we show the occurrence of combined VAMP7/ATG9 secretory events. VAMP7 localized, together with LC3 and ATG9, in vesicles moving anterogradely along the axon towards growth cones. VAMP7 knockout disrupted the autophagy response to drugs and starvation. Release of extracellular vesicles triggered by autophagy was impaired in VAMP7-knockout cells and autophagy-deficient cells were impaired in VAMP7 exocytosis. Secretomics showed that VAMP7-knockout cells were impaired in unconventional secretion of cytoplasmic, exosomal and mitochondrial proteins. We further found that autophagy stimulated neurite growth in a VAMP7-dependent manner. Furthermore, neurons still grew long axons in nutrient-restricted conditions and when treated with autophagy-inducing drugs. A nanobody directed against VAMP7 inhibited the effect of nutrient restriction. We propose that VAMP7-dependent autophagic secretion contributes to a resilience mechanism to preserve axonal growth in restriction conditions, as part of brain sparing occurring in growth restriction.

2020-12-10 | PXD014231 | Pride

Restoring Mitofusin balance in the nervous system prevents axonal degeneration in a CMT2A mouse model

Project description:MFN2 is a mitochondrial outer membrane protein that plays a pivotal role in mitochondrial dynamics in most tissues, yet mutations in MFN2 (which cause Charcot-Marie-Tooth disease type 2A) primarily affect the nervous system. We generated a transgenic mouse model of CMT2A which developed severe early-onset vision loss and neurological deficits, axonal degeneration without cell body loss, and cytoplasmic and axonal accumulations of fragmented mitochondria labeled for degradation. Mutant MFN2R94Q had a dominant negative effect on mitochondrial fusion if MFN1 was absent or at low levels, as in neurons. Finally we found that augmenting the level of MFN1 in the nervous system in vivo led to rescue of all phenotypes in mutant MFN2R94Q expressing mice. These data demonstrate that the MFN1:MFN2 ratio is a key determinant of tissue specificity in CMT2A, and indicates that augmentation of MFN1 in the nervous system is a viable therapeutic strategy for the disease.

2019-04-03 | GSE116863 | GEO

Myelin insulation as a risk factor for axonal degeneration in autoimmune demyelinating disease

Project description:Myelin insulation as a risk factor for axonal degeneration in autoimmune demyelinating disease

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