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Therapeutic implications of phosphorylation- and dephosphorylation-dependent factors of cAMP-response element-binding protein (CREB) in neurodegeneration

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Abstract

Neurodegeneration is a condition of the central nervous system (CNS) characterized by loss of neural structures and function. The most common neurodegenerative disorders (NDDs) include Alzheimer's disease (AD), Huntington’s disease (HD), amyotrophic lateral sclerosis (ALS), Parkinson’s disease (PD), multiple sclerosis (MS), motor neuron disorders, psychological disorders, dementia with vascular dementia (VaD), Lewy body dementia (DLB), epilepsy, cerebral ischemia, mental illness, and behavioral disorders. CREB (cAMP-response element-binding protein) represent a nuclear protein that regulates gene transcriptional activity. The primary focus of the review pertains to the exploration of CREB expression and activation within the context of neurodegenerative diseases, specifically in relation to the phosphorylation and dephosphorylation events that occur within the CREB signaling pathway under normal physiological conditions. The findings mentioned have contributed to the elucidation of the regulatory mechanisms governing CREB activity. Additionally, they have provided valuable insights into the potential mediation of diverse biological processes, such as memory consolidation and neuroprotective effects, by various related studies. The promotion of synaptic plasticity and neurodevelopment in the central nervous system through the targeting of CREB proteins has the potential to contribute to the prevention or delay of the onset of neurodegenerative disorders. Multiple drugs have been found to initiate downstream signaling pathways, leading to neuroprotective advantages in both animal model studies and clinical trials. The clinical importance of the cAMP-response element-binding protein (CREB) is examined in this article, encompassing its utility as both a predictive/prognostic marker and a target for therapeutic interventions.

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Abbreviations

ATF1:

Activation transcription factor 1

BDNF:

Brain-derived neurotrophic factor

bZIP:

Basic leucine zipper

CaMKIV:

Ca2+/calmodulin-dependent protein kinase IV

CaN:

Calcineurin

CREB:

CAMP-responsive element-binding protein

CREM:

CAMP-responsive element modulator

GPCRs:

G-protein-coupled receptors

JNK:

C-Jun N-terminal kinase pathway

KID:

Kinase inducible domain

MAPK:

Mitogen-activated protein kinase

NDDs:

Neurodegenerative disorders

NF-κB:

NF-kappa B, “nuclear factor kappa-light-chain-enhancer of activated B cells”

NGF:

Nerve growth factor

NMDARs:

N-Methyl-D-aspartate receptors

PACAP:

Pituitary adenylate cyclase-activating polypeptide

PKA:

Protein kinase A

PP-1:

Protein phosphatase-1

RTKs:

Receptor tyrosine kinases

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Acknowledgements

The authors are grateful to the Chitkara College of Pharmacy, Chitkara University, Rajpura, Patiala, Punjab, India for providing the necessary facilities to carry out the research work.

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  1. Chitkara College of Pharmacy, Chitkara University, Rajpura, Punjab, 140401, India

    Nilima Khakha, Heena Khan, Amarjot Kaur & Thakur Gurjeet Singh

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  1. Nilima Khakha
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  2. Heena Khan
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  3. Amarjot Kaur
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  4. Thakur Gurjeet Singh
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Conceptualization: TGS. Wrote the manuscript: NK, HK. Editing of the manuscript: HK, AK, TGS. Critically reviewed the article: TGS. Supervision: TGS. All authors read and approved the final manuscript.

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Correspondence to Thakur Gurjeet Singh.

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Khakha, N., Khan, H., Kaur, A. et al. Therapeutic implications of phosphorylation- and dephosphorylation-dependent factors of cAMP-response element-binding protein (CREB) in neurodegeneration. Pharmacol. Rep 75, 1152–1165 (2023). https://doi.org/10.1007/s43440-023-00526-9

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