Inactivated AMPK-α2 promotes the progression of diabetic brain damage by Cdk5 phosphorylation at Thr485 site

Li, Yan; Xiang, Qian; Yao, Yu-Han; Li, Jingjing; Wang, Yan; Li, Xianhui

doi:10.1016/j.biochi.2019.11.010

Cited by 11 publications

(5 citation statements)

References 31 publications

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“…The cyclin-dependent kinase CDK5 is important for neuronal development, survival, migration, differentiation, and metabolism [ 71 ]. CDK5 phosphorylates AMPKa2 at Thr485, which repressed its activity in the brain [ 39 ]. While we did not observe an interaction between CDK5 and AMPKa2 in the heart, CDK5 inhibition may be cardioprotective [ 24 ].…”

Section: Resultsmentioning

confidence: 99%

LncRNA LncHrt preserves cardiac metabolic homeostasis and heart function by modulating the LKB1-AMPK signaling pathway

et al. 2021

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Metabolic modulation is a promising therapeutic approach to prevent adverse remodeling of the ischemic heart. Because little is known about the involvement of long non-coding RNAs (lncRNAs) in regulating cardiac metabolism, we used unbiased transcriptome profiling in a mouse model of myocardial infarction (MI). We identified a novel cardiomyocyte-enriched lncRNA, called LncHrt, which regulates metabolism and the pathophysiological processes that lead to heart failure. AAV-based LncHrt overexpression protects the heart from MI as demonstrated by improved contractile function, preserved metabolic homeostasis, and attenuated maladaptive remodeling responses. RNA-pull down followed by mass spectrometry and RNA immunoprecipitation (RIP) identified SIRT2 as a LncHrt-interacting protein involved in cardiac metabolic regulation. Mechanistically, we established that LncHrt interacts with SIRT2 to preserve SIRT2 deacetylase activity by interfering with the CDK5 and SIRT2 interaction. This increases downstream LKB1-AMPK kinase signaling, which ameliorates functional and metabolic deficits. Importantly, we found the expression of the human homolog of mouse LncHrt was decreased in patients with dilated cardiomyopathy. Together, these studies identify LncHrt as a cardiac metabolic regulator that plays an essential role in preserving heart function by regulating downstream metabolic signaling pathways. Consequently, LncHrt is a potentially novel RNA-based therapeutic target for ischemic heart disease.

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Section: Resultsmentioning

confidence: 99%

LncRNA LncHrt preserves cardiac metabolic homeostasis and heart function by modulating the LKB1-AMPK signaling pathway

et al. 2021

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“…Pretreatment with metformin or Cdk5 inhibitor roscovitine promote the expression of AMPK by inhibiting Cdk5. 55 It has been suggested that metformin can mitigate different neurodegenerative diseases by modulating different signalling pathways including PD. 56 Furthermore, metformin attenuates cognitive dysfunction in mice with accelerated age by inhibiting calpain signalling and endoplasmic reticulum stress.…”

Section: Role Of Calpain/cdk5 Inhibitors In Pdmentioning

confidence: 99%

“…In vitro and vivo studies showed that Cdk5 inhibits AMPK leading to induction of apoptosis in the hippocampal neurons. Pretreatment with metformin or Cdk5 inhibitor roscovitine promote the expression of AMPK by inhibiting Cdk5 55 . It has been suggested that metformin can mitigate different neurodegenerative diseases by modulating different signalling pathways including PD 56 .…”

Section: Role Of Calpain/cdk5 Inhibitors In Pdmentioning

confidence: 99%

Cyclin‐dependent kinase 5 (CDK5) inhibitors in Parkinson disease

Alrouji,

Al‐kuraishy,

Al‐Gareeb

et al. 2024

J Cellular Molecular Medi

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Cyclin‐dependent kinase 5 (Cdk5) is a protein expressed in postmitotic neurons in the central nervous system (CNS). Cdk5 is activated by p35 and p39 which are neuron regulatory subunits. Cdk5/p35 complex is activated by calpain protease to form Cdk5/p35 which has a neuroprotective effect by regulating the synaptic plasticity and memory functions. However, exaggerated Cdk5 is implicated in different types of neurodegenerative diseases including Parkinson disease (PD). Therefore, modulation of Cdk5 signalling may mitigate PD neuropathology. Therefore, the aim of the present review was to discuss the critical role of Cdk5 in the pathogenesis of PD, and how Cdk5 inhibitors are effectual in the management of PD. In conclusion, overactivated Cdk5 is involved the development of neurodegeneration, and Cdk5/calpain inhibitors such as statins, metformin, fenofibrates and rosiglitazone can attenuate the progression of PD neuropathology.

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“…Circadian behavior (Zhou et al, 2022 ), learning disabilities (Kamiki et al, 2018 ), and aging (Spurrier et al, 2018 ) are also closely related to Cdk5. Diabetes induces brain damage by regulating Cdk5 phosphorylation (Li et al, 2020b ). Inhibition of Cdk5 improves glucose uptake in insulin-resistant neuronal cells via the ERK1/2 pathway (Manglani and Dey, 2022 ), and alleviates cognitive deficits caused by diabetes (Liu et al, 2019 ).…”

Section: Other Neurological Disordersmentioning

confidence: 99%

The role of Cdk5 in neurological disorders

Chen

et al. 2022

Front. Cell. Neurosci.

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Neurological disorders are a group of disorders with motor, sensory or cognitive damage, caused by dysfunction of the central or peripheral nervous system. Cyclin-dependent kinases 5 (Cdk5) is of vital significance for the development of the nervous system, including the migration and differentiation of neurons, the formation of synapses, and axon regeneration. However, when the nervous system is subject to pathological stimulation, aberrant activation of Cdk5 will induce abnormal phosphorylation of a variety of substrates, resulting in a cascade signaling pathway, and thus lead to pathological changes. Cdk5 is intimately related to the pathological mechanism of a variety of neurological disorders, such as A-β protein formation in Alzheimer’s disease, mitochondrial fragmentation in cerebral ischemia, and apoptosis of dopaminergic neurons in Parkinson’s disease. It is worth noting that Cdk5 inhibitors have been reported to have neuroprotective effects by inhibiting related pathological processes. Therefore, in this review, we will briefly introduce the physiological and pathological mechanisms of Cdk5 in the nervous system, focusing on the recent advances of Cdk5 in neurological disorders and the prospect of targeted Cdk5 for the treatment of neurological disorders.

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Inactivated AMPK-α2 promotes the progression of diabetic brain damage by Cdk5 phosphorylation at Thr485 site

Cited by 11 publications

References 31 publications

LncRNA LncHrt preserves cardiac metabolic homeostasis and heart function by modulating the LKB1-AMPK signaling pathway

LncRNA LncHrt preserves cardiac metabolic homeostasis and heart function by modulating the LKB1-AMPK signaling pathway

Cyclin‐dependent kinase 5 (CDK5) inhibitors in Parkinson disease

The role of Cdk5 in neurological disorders

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