Physiological and Pathological Roles of Cdk5: Potential Directions for Therapeutic Targeting in Neurodegenerative Disease

Allnutt, Annamarie; Waters, Ariana K; Kesari, Santosh; Yenugonda, Venkata Mahidhar

doi:10.1021/acschemneuro.0c00096

Cited by 60 publications

(64 citation statements)

References 148 publications

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“…P35, an activator of Cdk5, hydrolyses into p25 and subsequently binds to Cdk5 when Calpain is activated, causing abnormal activation of Cdk5. The Cdk5/p25 complex induces neurotoxicity, cell death and various diseases [39][40][41]. The results of the present study demonstrate the role of the above pathway in the regulation of p-SYN1 (ser-553); that is, microwave exposure induces higher levels of Calpain, which subsequently promotes Cdk5/p25 complex formation, potentially leading to the reduction of p-SYN1 (ser-553) as depicted in in Figure 9.…”

Section: Discussionsupporting

confidence: 54%

Low p-SYN1 (Ser-553) Expression Leads to Abnormal Neurotransmitter Release of GABA Induced by Up-Regulated Cdk5 after Microwave Exposure: Insights on Protection and Treatment of Microwave-Induced Cognitive Dysfunction

Zhi

Qiao²,

Zou

et al. 2021

CIMB

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With the wide application of microwave technology, concerns about its health impact have arisen. The signal transmission mode of the central nervous system and neurons make it particularly sensitive to electromagnetic exposure. It has been reported that abnormal release of amino acid neurotransmitters is mediated by alteration of p-SYN1 after microwave exposure, which results in cognitive dysfunction. As the phosphorylation of SYN1 is regulated by different kinases, in this study we explored the regulatory mechanisms of SYN1 fluctuations following microwave exposure and its subsequent effect on GABA release, aiming to provide clues on the mechanism of cognitive impairment caused by microwave exposure. In vivo studies with Timm and H&E staining were adopted and the results showed abnormality in synapse formation and neuronal structure, explaining the previously-described deficiency in cognitive ability caused by microwave exposure. The observed alterations in SYN1 level, combined with the results of earlier studies, indicate that SYN1 and its phosphorylation status (ser-553 and ser62/67) may play a role in the abnormal release of neurotransmitters. Thus, the role of Cdk5, the upstream kinase regulating the formation of p-SYN1 (ser-553), as well as that of MEK, the regulator of p-SYN1 (ser-62/67), were investigated both in vivo and in vitro. The results showed that Cdk5 was a negative regulator of p-SYN1 (ser-553) and that its up-regulation caused a decrease in GABA release by reducing p-SYN1 (ser-553). While further exploration still needed to elaborate the role of p-SYN1 (ser-62/67) for neurotransmitter release, MEK inhibition had was no impact on p-Erk or p-SYN1 (ser-62/67) after microwave exposure. In conclusion, the decrease of p-SYN1 (ser-553) may result in abnormalities in vesicular anchoring and GABA release, which is caused by increased Cdk5 regulated through Calpain-p25 pathway after 30 mW/cm2 microwave exposure. This study provided a potential new strategy for the prevention and treatment of microwave-induced cognitive dysfunction.

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Section: Discussionsupporting

confidence: 54%

Low p-SYN1 (Ser-553) Expression Leads to Abnormal Neurotransmitter Release of GABA Induced by Up-Regulated Cdk5 after Microwave Exposure: Insights on Protection and Treatment of Microwave-Induced Cognitive Dysfunction

Zhi

Qiao²,

Zou

et al. 2021

CIMB

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“…Various studies have reported the overexpression of cell cycle protein regulators, such as CDKs, in the vicinity of NFTs and senile plaques in the post-mortem brains of AD patients [68,90], indicating that the overexpression of the regulators of the cell cycle may be a characteristic feature of AD. Consistently, the administration of CDKIs (inhibitors of CDK1, 2, 4, 5, 7, 9) ameliorated AD symptoms in animal models [91][92][93][94][95][96], corroborating that the cell cycle and mitosis play an important role in AD development and could become important targets of drug research. In this sense, CDKIs have been suggested to be of potential relevance in the treatment of AD [93].…”

Section: Cell Cycle and Admentioning

confidence: 64%

p27, The Cell Cycle and Alzheimer´s Disease

García‐Osta

Dong

Moreno-Aliaga

et al. 2022

IJMS

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The cell cycle consists of successive events that lead to the generation of new cells. The cell cycle is regulated by different cyclins, cyclin-dependent kinases (CDKs) and their inhibitors, such as p27Kip1. At the nuclear level, p27Kip1 has the ability to control the evolution of different phases of the cell cycle and oppose cell cycle progression by binding to CDKs. In the cytoplasm, diverse functions have been described for p27Kip1, including microtubule remodeling, axonal transport and phagocytosis. In Alzheimer’s disease (AD), alterations to cycle events and a purported increase in neurogenesis have been described in the early disease process before significant pathological changes could be detected. However, most neurons cannot progress to complete their cell division and undergo apoptotic cell death. Increased levels of both the p27Kip1 levels and phosphorylation status have been described in AD. Increased levels of Ab42, tau hyperphosphorylation or even altered insulin signals could lead to alterations in p27Kip1 post-transcriptional modifications, causing a disbalance between the levels and functions of p27Kip1 in the cytoplasm and nucleus, thus inducing an aberrant cell cycle re-entry and alteration of extra cell cycle functions. Further studies are needed to completely understand the role of p27Kip1 in AD and the therapeutic opportunities associated with the modulation of this target.

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“…Cdk5 activity is crucial after toxic stimuli to avoid initiation of apoptosis, cytoskeletal remodeling, detachment from the glomerular basement membrane, and, eventually, loss of podocytes in the urine. Several studies on Cdk5 in neurological and oncological disorders showed good transferability of results gained in mice to human disease [ 53 , 54 ]. Consequently, it is tempting to speculate that activation of Cdk5 could be a novel therapeutic approach in human inflammatory glomerular disease.…”

Section: Discussionmentioning

confidence: 99%

The Atypical Cyclin-Dependent Kinase 5 (Cdk5) Guards Podocytes from Apoptosis in Glomerular Disease While Being Dispensable for Podocyte Development

Mangold

Pippin

Unnersjoe-Jess

et al. 2021

Cells

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Cyclin-dependent kinase 5 (Cdk5) is expressed in terminally differentiated cells, where it drives development, morphogenesis, and survival. Temporal and spatial kinase activity is regulated by specific activators of Cdk5, dependent on the cell type and environmental factors. In the kidney, Cdk5 is exclusively expressed in terminally differentiated glomerular epithelial cells called podocytes. In glomerular disease, signaling mechanisms via Cdk5 have been addressed by single or combined conventional knockout of known specific activators of Cdk5. A protective, anti-apoptotic role has been ascribed to Cdk5 but not a developmental phenotype, as in terminally differentiated neurons. The effector kinase itself has never been addressed in animal models of glomerular disease. In the present study, conditional and inducible knockout models of Cdk5 were analyzed to investigate the role of Cdk5 in podocyte development and glomerular disease. While mice with podocyte-specific knockout of Cdk5 had no developmental defects and regular lifespan, loss of Cdk5 in podocytes increased susceptibility to glomerular damage in the nephrotoxic nephritis model. Glomerular damage was associated with reduced anti-apoptotic signals in Cdk5-deficient mice. In summary, Cdk5 acts primarily as master regulator of podocyte survival during glomerular disease and—in contrast to neurons—does not impact on glomerular development or maintenance.

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Physiological and Pathological Roles of Cdk5: Potential Directions for Therapeutic Targeting in Neurodegenerative Disease

Cited by 60 publications

References 148 publications

Low p-SYN1 (Ser-553) Expression Leads to Abnormal Neurotransmitter Release of GABA Induced by Up-Regulated Cdk5 after Microwave Exposure: Insights on Protection and Treatment of Microwave-Induced Cognitive Dysfunction

Low p-SYN1 (Ser-553) Expression Leads to Abnormal Neurotransmitter Release of GABA Induced by Up-Regulated Cdk5 after Microwave Exposure: Insights on Protection and Treatment of Microwave-Induced Cognitive Dysfunction

p27, The Cell Cycle and Alzheimer´s Disease

The Atypical Cyclin-Dependent Kinase 5 (Cdk5) Guards Podocytes from Apoptosis in Glomerular Disease While Being Dispensable for Podocyte Development

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