AAV-Mediated Expression of Dominant-Negative ULK1 Increases Neuronal Survival and Enhances Motor Performance in the MPTP Mouse Model of Parkinson’s Disease

Balke, Dirk; Tatenhorst, Lars; Dambeck, Vivian; Ribas, Vinícius Toledo; Vahsen, Björn Friedhelm; Michel, Uwe; Bähr, Mathias; Lingor, Paul

doi:10.1007/s12035-019-01744-0

Cited by 16 publications

(37 citation statements)

References 55 publications

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“…However, these results were merely descriptive, leaving the functional role of ULK1 in axonal degeneration unclear. Recently, we have demonstrated ULK1.DN-mediated protection of dopaminergic nigral neurons and nigro-striatal projections against MPTP-induced degeneration in a mouse model of Parkinson's disease [17]. Here, we significantly advance these findings, providing to our best knowledge the first evidence that inhibition of ULK1 function protects three different types of neurons against axonal degeneration after traumatic axonal lesion, both in an acute and chronic paradigm.…”

Section: Discussionmentioning

confidence: 63%

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

et al. 2020

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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.

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Section: Discussionmentioning

confidence: 63%

“…Cloning and production of AAV.ULK1.DN (corresponding to amino acids 829–1051 of ULK1, connected to an N-terminal myc-tag [ 15 ]) and AAV.CTRL was performed as reported previously [ 17 ]. In addition, AAV.EGFP [ 18 , 19 ] was used in some in vivo experiments.…”

Section: Methodsmentioning

confidence: 99%

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

et al. 2020

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“…Kemp et al reported that UV radiation and chemical carcinogens enhance STING-dependent IRF3 activation, which exacerbates the symptoms of autoimmunity. Of note, ULK1 negatively regulates STING [95]. The natural immune response that is induced by ultraviolet light can be enhanced by downregulating the expression of ULK1 in keratinocytes [95,96].…”

Section: The Noncanonical Role Of Ulk1mentioning

confidence: 99%

“…Of note, ULK1 negatively regulates STING [95]. The natural immune response that is induced by ultraviolet light can be enhanced by downregulating the expression of ULK1 in keratinocytes [95,96]. The lack of ULK1 tends to result in impaired RBC macrocytosis and mitochondrial clearance [88], which leads to a shortened life of RBCs [97].…”

Section: The Noncanonical Role Of Ulk1mentioning

confidence: 99%

A Review of ULK1-Mediated Autophagy in Drug Resistance of Cancer

Liu

Liao

et al. 2020

Cancers

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The difficulty of early diagnosis and the development of drug resistance are two major barriers to the successful treatment of cancer. Autophagy plays a crucial role in several cellular functions, and its dysregulation is associated with both tumorigenesis and drug resistance. Unc-51-like kinase 1 (ULK1) is a serine/threonine kinase that participates in the initiation of autophagy. Many studies have indicated that compounds that directly or indirectly target ULK1 could be used for tumor therapy. However, reports of the therapeutic effects of these compounds have come to conflicting conclusions. In this work, we reviewed recent studies related to the effects of ULK1 on the regulation of autophagy and the development of drug resistance in cancers, with the aim of clarifying the mechanistic underpinnings of this therapeutic target.

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“…Neuronal death was not only observed in PD mice, but also accompanied by certain adverse reactions, such as immunosuppression, leukopenia, and respiratory infection. Thus, AMPK-mTOR-mediated autophagy and apoptosis signaling pathways might be potential targets for treating PD [ 146 , 147 , 148 , 149 ]. Other studies have shown that transfection of the stable Beclin1 virus plasmid into cells activated autophagy, reduced the accumulation of protein aggregates, and decreased the incidence of PD [ 148 , 150 ].…”

Section: Autophagy and Nddsmentioning

confidence: 99%

Melatonin and Autophagy in Aging-Related Neurodegenerative Diseases

Luo

Sandhu

Rungratanawanich

et al. 2020

IJMS

104

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With aging, the nervous system gradually undergoes degeneration. Increased oxidative stress, endoplasmic reticulum stress, mitochondrial dysfunction, and cell death are considered to be common pathophysiological mechanisms of various neurodegenerative diseases (NDDs) such as Alzheimer’s disease (AD), Parkinson’s disease (PD), Huntington’s disease (HD), organophosphate-induced delayed neuropathy (OPIDN), and amyotrophic lateral sclerosis (ALS). Autophagy is a cellular basic metabolic process that degrades the aggregated or misfolded proteins and abnormal organelles in cells. The abnormal regulation of neuronal autophagy is accompanied by the accumulation and deposition of irregular proteins, leading to changes in neuron homeostasis and neurodegeneration. Autophagy exhibits both a protective mechanism and a damage pathway related to programmed cell death. Because of its “double-edged sword”, autophagy plays an important role in neurological damage and NDDs including AD, PD, HD, OPIDN, and ALS. Melatonin is a neuroendocrine hormone mainly synthesized in the pineal gland and exhibits a wide range of biological functions, such as sleep control, regulating circadian rhythm, immune enhancement, metabolism regulation, antioxidant, anti-aging, and anti-tumor effects. It can prevent cell death, reduce inflammation, block calcium channels, etc. In this review, we briefly discuss the neuroprotective role of melatonin against various NDDs via regulating autophagy, which could be a new field for future translational research and clinical studies to discover preventive or therapeutic agents for many NDDs.

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AAV-Mediated Expression of Dominant-Negative ULK1 Increases Neuronal Survival and Enhances Motor Performance in the MPTP Mouse Model of Parkinson’s Disease

Cited by 16 publications

References 55 publications

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

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

A Review of ULK1-Mediated Autophagy in Drug Resistance of Cancer

Melatonin and Autophagy in Aging-Related Neurodegenerative Diseases

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