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Dissecting the Relationship Between Neuropsychiatric and Neurodegenerative Disorders

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Abstract

Neurodegenerative diseases (NDDs) and neuropsychiatric disorders (NPDs) are two common causes of death in elderly people, which includes progressive neuronal cell death and behavioral changes. NDDs include Alzheimer’s disease, Parkinson’s disease, Huntington’s disease, amyotrophic lateral sclerosis, multiple sclerosis, and motor neuron disease, characterized by cognitive defects and memory impairment, whereas NPDs include depression, seizures, migraine headaches, eating disorders, addictions, palsies, major depressive disorders, anxiety, and schizophrenia, characterized by behavioral changes. Mounting evidence demonstrated that NDDs and NPDs share an overlapping mechanism, which includes post-translational modifications, the microbiota–gut–brain axis, and signaling events. Mounting evidence demonstrated that various drug molecules, namely, natural compounds, repurposed drugs, multitarget directed ligands, and RNAs, have been potentially implemented as therapeutic agents against NDDs and NPDs. Herein, we highlighted the overlapping mechanism, the role of anxiety/stress-releasing factors, cytosol-to-nucleus signaling, and the microbiota–gut–brain axis in the pathophysiology of NDDs and NPDs. We summarize the therapeutic application of natural compounds, repurposed drugs, and multitarget-directed ligands as therapeutic agents. Lastly, we briefly described the application of RNA interferences as therapeutic agents in the pathogenesis of NDDs and NPDs.

Graphical Abstract

Neurodegenerative diseases and neuropsychiatric diseases both share a common signaling molecule and molecular phenomenon, namely, pro-inflammatory cytokines, γCaMKII and MAPK/ERK, chemokine receptors, BBB permeability, and the gut–microbiota–brain axis. Studies have demonstrated that any alterations in the signaling mentioned above molecules and molecular phenomena lead to the pathophysiology of neurodegenerative diseases, namely, Alzheimer’s disease, Parkinson’s disease, Huntington’s disease, and amyotrophic lateral sclerosis, and neuropsychiatric disorders, such as bipolar disorder, schizophrenia, depression, anxiety, autism spectrum disorder, and post-traumatic stress disorder.

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Abbreviations

NDDs:

Neurodegenerative diseases

NPDs:

Neuropsychiatric disorders

AD:

Alzheimer’s disease

PD:

Parkinson’s disease

HD:

Huntington's disease

ALS:

Amyotrophic lateral sclerosis

CNS:

Central nervous system

miRNA:

MicroRNA

ncRNA:

Non-coding RNAs

PTM:

Post-translational modifications

HATs:

Histone acetyltransferase

HDACs:

Histone deacetylases

DNMTs:

DNA methyltransferases

TSPO:

The 18-kDa translocator protein

mTOR:

Mammalian target of rapamycin

Aβ:

β-Amyloid

CRF:

Corticotropin-releasing factor

TNFα:

Tumor necrosis factor alpha

MCP-1:

Monocyte chemoattractant protein-1

CCL2:

Chemokine (C-C motif) ligand 2

OXTR:

Oxytocin receptor gene

TCM:

Traditional Chinese medicine

SSRIs:

Selective serotonin reuptake inhibitors

IL-1α:

Interleukin 1 alpha

IL-1β:

Interleukin 1 beta

IL-6:

Interleukin 6

BDNF:

Brain-derived neurotropic factor

ASD:

Autism spectrum disorder

TLR4:

Toll-like receptor 4

MyD88:

Myeloid differentiation primary response 88

NF-κB:

Nuclear factor kappa B

γCaMKII:

γ-Ca2+/calmodulin-dependent protein kinase II

CREB:

cAMP response element-binding protein

GluN2B:

Glutamate receptor subunit epsilon-2

PSD95:

Postsynaptic density protein 95

PKA:

Protein kinase A

MAPK:

Mitogen-activated protein kinase

ERK:

Serine/threonine protein kinase

ROS:

Reactive oxygen species

PET:

Positron emission tomography

c/EBPβ:

CCAAT/enhancer-binding protein beta

UBR5:

Ubiquitin protein ligase E3 component N-Recognin 5

iPSCs:

Induced pluripotent stem cells

ASB17:

Ankyrin repeat, and SOCS box protein 17

TDP-43:

TAR DNA-binding protein 43

LTN1:

Listerin1

CUL3:

Cullin3

MeCP2:

Methyl CpG binding protein 2

CAM:

Complementary and alternative medicine

MTDL:

Multitarget directed ligand

NSAIDs:

Non-steroidal anti-inflammatory drugs

GLP-1:

Glucagon-like peptide-1

PPAR-γ:

Peroxisome proliferator- activated receptor gamma

SDAM:

Serotonin–dopamine activity modulators

TLR-2:

Toll-like receptor-2

NADPH:

Nicotinamide adenine dinucleotide phosphate

CDK5:

Cyclin-dependent kinase 5

TGF-β:

Transforming growth factor beta

GRM4:

Glutamate receptor 4, metabotropic

MALAT1:

Metastasis-related lung adenocarcinoma transcript 1

NEAT1:

Nuclear enriched abundant transcript 1

DISC2:

Disrupted in schizophrenia 2

BDNF-AS:

Brain-derived neurotrophic factor antisense

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Acknowledgements

We would like to thank the senior management of Delhi Technological University for their constant support and guidance.

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  1. Rohan Gupta, Dia Advani, and Divya Yadav contributed equally to this work.

Authors and Affiliations

  1. Molecular Neuroscience and Functional Genomics Laboratory, Department of Biotechnology, Delhi Technological University, Shahbad Daulatpur, Bawana Road, New Delhi, Delhi, 110042, India

    Rohan Gupta, Dia Advani, Divya Yadav, Rashmi K Ambasta & Pravir Kumar

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Contributions

The project is conceived by RG and PK. The data collected by RG, DA, and DY. The art work is done by RG and DA. The data were arranged and analyzed by all authors. The paper is written by RG, DA, DY, RKA, and PK. All authors have read the paper and expressed no objection to submit.

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Highlights

• Stress/anxiety-releasing factors, namely, serotonin, norepinephrine, and corticotrophins, in NPDs and NDDs

• Microbiota–gut–brain axis is a potential therapeutic target in the NPDs and NDDs

• Therapeutic role of γCaMKII and MAPK/ERK signaling in NPDs and NDDs

• Therapeutic considerations of post-translational modification in the pathophysiology of NPDs and NDDs

• Natural compounds, MTDL, and RNAs as therapeutic agents against NPDs and NDDs

• Potential involvement of repurposed drugs in the treatment of NPDs and NDDs

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Gupta, R., Advani, D., Yadav, D. et al. Dissecting the Relationship Between Neuropsychiatric and Neurodegenerative Disorders. Mol Neurobiol 60, 6476–6529 (2023). https://doi.org/10.1007/s12035-023-03502-9

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