MEC17‐induced α‐tubulin acetylation restores mitochondrial transport function and alleviates axonal injury after intracerebral hemorrhage in mice

Yang, Yang; Chen, Xuezhu; Feng, Zhaochi; Cai, Xiaoyan; Zhu, Xiaoming; Cao, Ming; Yang, Likun; Chen, Yujie; Wang, Yuhai; Feng, Hua

doi:10.1111/jnc.15493

Cited by 21 publications

(14 citation statements)

References 43 publications

(59 reference statements)

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“…Several studies including ours have pointed to the validity of this approach. For example, targeting MTs by increasing their acetylation, which is frequently linked to MT stability, protects axons and transport of mitochondria in a mouse trauma model caused by intracerebral haemorrhage (Yang et al, 2022). Furthermore, manipulation of MTs by the use of MT-targeting agents (MTAs) has proven valuable in the context of age-related neurodegenerative diseases, as suggested by recent reports highlighting the beneficial therapeutic effects of MT-stabilising compounds such as Epothilone D in several models of tauopathies (Varidaki et al, 2018, Fernandez-Valenzuela et al, 2020, Wordeman and Vicente, 2021).…”

Section: Discussionmentioning

confidence: 99%

Microtubule decay is a driver of neuronal ageing and a promising target for intervention

Okenve-Ramos

Gosling

Chojnowska-Monga

et al. 2023

Preprint

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Natural ageing is accompanied by a decline in motor, sensory and cognitive functions, all impacting life quality. Ageing is the predominant risk factor for many neurodegenerative diseases, including Parkinson's and Alzheimer's disease. We need therefore to gain a better understanding of the cellular and physiological processes underlying age-related neuronal decay. However, gaining this understanding is a slow process due to the long time required to age mammalian or vertebrate model animals. Here we introduce a new cellular model within the Drosophila brain where neurons show typical ageing hallmarks known from the primate brain, including axonal swellings, cytoskeletal decay, a reduction in axonal calibre and morphological changes arising at synaptic terminals. In the fly brain, these changes occur within just a few weeks, ideal to study the underlying mechanisms. We observe that decay of the neuronal microtubule cytoskeleton clearly precedes other ageing hallmarks. We show that the microtubule-binding factors Tau, EB1 and Shot, are necessary for microtubule maintenance in axons and synapses. Their functional loss during ageing triggers microtubule bundle decay followed by the decline in axons and synapses. Genetic manipulations that improve microtubule networks, slow down other neuronal ageing hallmarks and confer aged specimens with the ability to outperform age-matched controls. Our work suggests therefore that microtubule networks are a key lesion site in ageing neurons and offer promising opportunities to improve neuronal decay in advanced age.

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Section: Discussionmentioning

confidence: 99%

Microtubule decay is a driver of neuronal ageing and a promising target for intervention

Okenve-Ramos

Gosling

Chojnowska-Monga

et al. 2023

Preprint

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“… 30 Changes in the axonal cytoskeleton after ICH not only impact the physical structure of the axon but also mitochondrial transport and function leading to degeneration. 31 Recent studies have suggested that the inhibition of histone deacetylases (HDACs) with scriptaid or conditional knockout of HDAC2 in microglia can reduce ICH-induced neuroinflammation and WM injury in mice. 32 Other studies have targeted neuroinflammation with the antibiotic and inhibitor of microglial activation minocycline in piglets, 33 and the sphingosine-1-phosphate receptor modulator FTY720/fingolimod in mice.…”

Section: Haematomamentioning

confidence: 99%

“…AVM, arteriovenous malformations; BBB, blood-brain barrier; CAA, cerebral amyloid angiopathy; CCM, cerebral cavernous malformation; COL4A1, α1 chain of collagen type IV; ICH, intracerebral haemorrhage; L-NAME, N ω -nitro-L-arginine methyl ester. (A) Rodent models Model Aetiological or pathophysiological mechanisms addressed, translational value Autologous blood injection Endogenous haematoma clearance 26 , 28 , 29 , 53 White matter injury and axonal degeneration 30 , 100 Cell death 29 , 51 , 101 , 102 Perihaematomal oedema 49 , 51 , 53 , 101 , 102 BBB impairment 22 , 45 , 47 , 49 Inflammation 28 , 49 , 51 , 52 , 53 , 101 , 102 , 103 Immunosuppression 58 Cardiac complications 63 , 64 Can be combined with comorbidities: angiotensin II infusion + hyperglycaemia (incl. haematoma expansion), 22 hyperglycaemia 102 Collagenase injection Anticoagulation 12 , 13 Endogenous haematoma clearance 26 , …”

Section: Limitations Of Animal Modelsmentioning

confidence: 99%

Novel targets, treatments, and advanced models for intracerebral haemorrhage

Zille¹,

Farr²,

Keep³

et al. 2022

eBioMedicine

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“…Evaluation of ATP Levels. ATP in tissues around the haematoma and culture cells was measured using an ATP assay kit (ab83355; Abcam) as described previously [30]. Briefly, tissues or cells were washed in cold PBS, homogenised, and centrifuged to collect the supernatant, and the samples were mixed with assay buffer.…”

Section: Mitochondrial Membrane Potential and Mitochondrialmentioning

confidence: 99%

Docosahexaenoic Acid Alleviates Brain Damage by Promoting Mitophagy in Mice with Ischaemic Stroke

Sun

Zhang

Deng

et al. 2022

Oxidative Medicine and Cellular Longevity

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Mitophagy, the selective removal of damaged mitochondria through autophagy, is crucial for mitochondrial turnover and quality control. Docosahexaenoic acid (DHA), an essential omega-3 fatty acid, protects mitochondria in various diseases. This study aimed to investigate the neuroprotective role of DHA in ischaemic stroke models in vitro and in vivo and its involvement in mitophagy and mitochondrial dysfunction. A mouse model of ischaemic stroke was established through middle cerebral artery occlusion (MCAO). To simulate ischaemic stroke in vitro, PC12 cells were subjected to oxygen–glucose deprivation (OGD). Immunofluorescence analysis, western blotting (WB), electron microscopy (EM), functional behavioural tests, and Seahorse assay were used for analysis. DHA treatment significantly alleviated the brain infarction volume, neuronal apoptosis, and behavioural dysfunction in mice with ischaemic stroke. In addition, DHA enhanced mitophagy by significantly increasing the number of autophagosomes and LC3-positive mitochondria in neurons. The Seahorse assay revealed that DHA increased glutamate and succinate metabolism in neurons after ischaemic stroke. JC-1 and MitoSox staining, and evaluation of ATP levels indicated that DHA-induced mitophagy alleviated reactive oxygen species (ROS) accumulation and mitochondrial injury. Mechanistically, DHA improved mitochondrial dynamics by increasing the expression of dynamin-related protein 1 (Drp1), LC3, and the mitophagy clearance protein Pink1/Parkin. Mdivi-1, a specific mitophagy inhibitor, abrogated the neuroprotective effects of DHA, indicating that DHA protected neurons by enhancing mitophagy. Therefore, DHA can protect against neuronal apoptosis after stroke by clearing the damaged mitochondria through Pink1/Parkin-mediated mitophagy and by alleviating mitochondrial dysfunction.

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MEC17‐induced α‐tubulin acetylation restores mitochondrial transport function and alleviates axonal injury after intracerebral hemorrhage in mice

Cited by 21 publications

References 43 publications

Microtubule decay is a driver of neuronal ageing and a promising target for intervention

Microtubule decay is a driver of neuronal ageing and a promising target for intervention

Novel targets, treatments, and advanced models for intracerebral haemorrhage

Docosahexaenoic Acid Alleviates Brain Damage by Promoting Mitophagy in Mice with Ischaemic Stroke

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