Autophagy lipidation machinery regulates axonal microtubule dynamics but is dispensable for survival of mammalian neurons

Negrete-Hurtado, Albert; Overhoff, Melina; Bera, Sujoy; Bruyckere, Elodie De; Schätzmüller, K.; Kye, Min Jeong; Qin, Chuan; Lammers, Michael; Kondylis, Vangelis; Neundorf, Ines; Kononenko, Natalia L.

doi:10.1038/s41467-020-15287-9

Cited by 24 publications

(41 citation statements)

References 70 publications

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“…It means conjugation of the cytosolic LC3-I protein to phosphatidylethanolamine in the phagophore membrane to form LC3-II, which is one of the markers of autophagic vesicles (Yoshii and Mizushima, 2017 ). Recently, it has been demonstrated that autophagy lipidation machinery has a non-canonical, autophagy-independent function in regulating axonal microtubule dynamics (Negrete-Hurtado et al, 2020 ). ATG proteins involved in lipid conjugation of LC3 facilitate microtubule-dependent axonal transport.…”

Section: Selected Aspects Of Cellular Senescence and Their Role In Brmentioning

confidence: 99%

Cellular Senescence in Brain Aging

Sikora

Bielak-Żmijewska

Dudkowska

et al. 2021

Front. Aging Neurosci.

133

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Aging of the brain can manifest itself as a memory and cognitive decline, which has been shown to frequently coincide with changes in the structural plasticity of dendritic spines. Decreased number and maturity of spines in aged animals and humans, together with changes in synaptic transmission, may reflect aberrant neuronal plasticity directly associated with impaired brain functions. In extreme, a neurodegenerative disease, which completely devastates the basic functions of the brain, may develop. While cellular senescence in peripheral tissues has recently been linked to aging and a number of aging-related disorders, its involvement in brain aging is just beginning to be explored. However, accumulated evidence suggests that cell senescence may play a role in the aging of the brain, as it has been documented in other organs. Senescent cells stop dividing and shift their activity to strengthen the secretory function, which leads to the acquisition of the so called senescence-associated secretory phenotype (SASP). Senescent cells have also other characteristics, such as altered morphology and proteostasis, decreased propensity to undergo apoptosis, autophagy impairment, accumulation of lipid droplets, increased activity of senescence-associated-β-galactosidase (SA-β-gal), and epigenetic alterations, including DNA methylation, chromatin remodeling, and histone post-translational modifications that, in consequence, result in altered gene expression. Proliferation-competent glial cells can undergo senescence both in vitro and in vivo, and they likely participate in neuroinflammation, which is characteristic for the aging brain. However, apart from proliferation-competent glial cells, the brain consists of post-mitotic neurons. Interestingly, it has emerged recently, that non-proliferating neuronal cells present in the brain or cultivated in vitro can also have some hallmarks, including SASP, typical for senescent cells that ceased to divide. It has been documented that so called senolytics, which by definition, eliminate senescent cells, can improve cognitive ability in mice models. In this review, we ask questions about the role of senescent brain cells in brain plasticity and cognitive functions impairments and how senolytics can improve them. We will discuss whether neuronal plasticity, defined as morphological and functional changes at the level of neurons and dendritic spines, can be the hallmark of neuronal senescence susceptible to the effects of senolytics.

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Section: Selected Aspects Of Cellular Senescence and Their Role In Brmentioning

confidence: 99%

Cellular Senescence in Brain Aging

Sikora

Bielak-Żmijewska

Dudkowska

et al. 2021

Front. Aging Neurosci.

133

View full text Add to dashboard Cite

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“…ER stress in chronic neurodegenerative disorders often stimulates autophagic activities, however, failure in clearing the aggregated proteins and the impairment of UPR or autophagy lead to the accumulation of misfolded proteins and the progression of neurodegeneration [40]. Impairment of autophagy via the knockdown of AuTophaGy(ATG)-related proteins ATG1, -2, -6, or -18 impeded synaptic development [41], impaired axonal integrity via altering microtubules stability and underlaid the onset and progression of various neurodegenerative disorders [42]. Autophagy-deficient mice showed neuronal defects and an impairment of autophagy was found to be associated with neurodegenerative diseases such as ALS, PD, AD and prion diseases [39,40].…”

Section: Interaction Between Er Stress Autophagy and Neurodegenerationmentioning

confidence: 99%

Endoplasmic Reticulum Stress and Unfolded Protein Response in Neurodegenerative Diseases

Ghemrawi

Khair

2020

IJMS

173

102

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The endoplasmic reticulum (ER) is an important organelle involved in protein quality control and cellular homeostasis. The accumulation of unfolded proteins leads to an ER stress, followed by an adaptive response via the activation of the unfolded protein response (UPR), PKR-like ER kinase (PERK), inositol-requiring transmembrane kinase/endoribonuclease 1α (IRE1α) and activating transcription factor 6 (ATF6) pathways. However, prolonged cell stress activates apoptosis signaling leading to cell death. Neuronal cells are particularly sensitive to protein misfolding, consequently ER and UPR dysfunctions were found to be involved in many neurodegenerative diseases including Alzheimer’s disease, Parkinson’s disease, amyotrophic lateral sclerosis and prions diseases, among others characterized by the accumulation and aggregation of misfolded proteins. Pharmacological UPR modulation in affected tissues may contribute to the treatment and prevention of neurodegeneration. The association between ER stress, UPR and neuropathology is well established. In this review, we provide up-to-date evidence of UPR activation in neurodegenerative disorders followed by therapeutic strategies targeting the UPR and ameliorating the toxic effects of protein unfolding and aggregation.

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“…The importance of preventive or therapeutic autophagy regulation in neurodegenerative diseases is still debated (Bar-Yosef et al, 2019;Maiuri and Kroemer, 2019;Park et al, 2020;Suomi and Mc Williams, 2020). Negrete-Hurtado et al (2020) reported in ATG5 KO mice brain, a non canonical role of ATG proteins and that lipidation machinery is not required for neuronal survival. Indeed, the main function of ATG-induced LC3 lipidation is to regulate microtubular dynamic in en passant boutons.…”

Section: Resultsmentioning

confidence: 99%

Natural Compounds and Autophagy: Allies Against Neurodegeneration

Stacchiotti

Corsetti

2020

Front. Cell Dev. Biol.

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Prolonging the healthy life span and limiting neurological illness are imperative goals in gerontology. Age-related neurodegeneration is progressive and leads to severe diseases affecting motility, memory, cognitive function, and social life. To date, no effective treatments are available for neurodegeneration and irreversible neuronal loss. Bioactive phytochemicals could represent a natural alternative to ensure active aging and slow onset of neurodegenerative diseases in elderly patients. Autophagy or macroautophagy is an evolutionarily conserved clearing process that is needed to remove aggregateprone proteins and organelles in neurons and glia. It also is crucial in synaptic plasticity. Aberrant autophagy has a key role in aging and neurodegeneration. Recent evidence indicates that polyphenols like resveratrol and curcumin, flavonoids, like quercetin, polyamine, like spermidine and sugars, like trehalose, limit brain damage in vitro and in vivo. Their common mechanism of action leads to restoration of efficient autophagy by dismantling misfolded proteins and dysfunctional mitochondria. This review focuses on the role of dietary phytochemicals as modulators of autophagy to fight Alzheimer's and Parkinson's diseases, fronto-temporal dementia, amyotrophic lateral sclerosis, and psychiatric disorders. Currently, most studies have involved in vitro or preclinical animal models, and the therapeutic use of phytochemicals in patients remains limited.

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Autophagy lipidation machinery regulates axonal microtubule dynamics but is dispensable for survival of mammalian neurons

Cited by 24 publications

References 70 publications

Cellular Senescence in Brain Aging

Cellular Senescence in Brain Aging

Endoplasmic Reticulum Stress and Unfolded Protein Response in Neurodegenerative Diseases

Natural Compounds and Autophagy: Allies Against Neurodegeneration

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