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Role of JAK-STAT and PPAR-Gamma Signalling Modulators in the Prevention of Autism and Neurological Dysfunctions

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Abstract

The Janus-kinase (JAK) and signal transducer activator of transcription (STAT) signalling pathways regulate gene expression and control various factors involved in normal physiological functions such as cell proliferation, neuronal development, and cell survival. JAK activation phosphorylates STAT3 in astrocytes and microglia, and this phosphorylation has been linked to mitochondrial damage, apoptosis, neuroinflammation, reactive astrogliosis, and genetic mutations. As a regulator, peroxisome proliferator-activated receptor gamma (PPAR-gamma), in relation to JAK-STAT signalling, prevents this phosphorylation and aids in the treatment of the above-mentioned neurocomplications. Changes in cellular signalling may also contribute to the onset and progression of autism. Thus, PPAR-gamma agonist upregulation may be associated with JAK-STAT signal transduction downregulation. It may also be responsible for attenuating neuropathological changes by stimulating SOCS3 or involving RXR or SMRT, thereby reducing transcription of the various cytokine proteins and genes involved in neuronal damage. Along with JAK-STAT inhibitors, PPAR-gamma agonists could be used as target therapeutic interventions for autism. This research-based review explores the potential involvement and mutual regulation of JAK-STAT and PPAR-gamma signalling in controlling multiple pathological factors associated with autism.

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Abbreviations

AIMs:

Abnormal involuntary movement

Akt:

Protein kinase b

ARID1:

AT-rich interaction domain 1B

ASD:

ASD

BBB:

Blood brain barrier

BND:

Brain-derived neurotrophic factor

BTBR:

BTBR T + Itpr3tf/J strain

BTIC:

Brain tumour initiating cells

CASP:

Caspase

CAT:

Catalase

CCL:

Chemokine receptor ligand

CXCL:

Chemokine receptor

DAT:

Dopamine transporter

DC:

Dendritic cells

DHA:

Docosahexaenoic acid

EAE:

Experimental allergic encephalomyelitis

EMF:

Electromagnetic fields

ETC:

Electron transport chain

Fmr1-KO:

Fragile X mental retardation 1 knockout

FXS:

Fragile-x-syndrome

GPx:

Glutathione peroxidase

GFAP:

Glial fibrillary acidic protein

H2O2:

Hydrogen peroxide

ID:

Intellectual disabilities

IDD:

Intellectual developmental disorders

IL:

Interleukins

INFg:

Interferon gamma

iNOS:

Nitric oxide synthase

JAK:

Janus kinase

LEPR:

Leptin precursor receptor

LPS:

Lipopolysaccharide

LTD:

Long-term depression

METH:

Methamphetamine

MitoQ:

Mitochondria targeted antioxidant

mtROS:

Mitochondrial reactive oxygen species

NADPH:

Nicotinamide adenine dinucleotide phosphate

NASH:

Non-alcoholic steatohepatitis

NLN:

Neuroligin

NMDAR:

N-methyl-D-aspartate receptor

Nox oxidase:

NADPH oxidase

NSC:

Neural stem cells

OGD:

Oxygen glucose deprived

OH:

Hydroxyl

PD:

Parkinson disease

PLC:

Phospholipase C

PPARγ:

Peroxisome proliferation-activated receptor gamma

ROS:

Reactive oxygen species

RXR:

Retinoid-x-receptors

SAE:

Sepsis-associated encephalopathy

SERT:

Serotonin transporter

SOD:

Superoxide dismutase

SOCS:

Suppressor of cytokine signalling

STAT:

Signal transducer and activator of transcription

SVZ:

Subventricular zone

TBI:

Traumatic brain injury

TNF-α:

Tumour necrotic factor-alpha

VPA:

Valproic acid

X-ALD:

X-linked adrenoleukodystrophy

ROS-R:

Reactive oxygen species-receptor

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Acknowledgements

The authors express their gratitude to Chairman, Mr. Parveen Garg, and Director, Dr. G. D. Gupta, ISF College of Pharmacy, Moga (Punjab), India, for their excellent vision and support.

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  1. Neuropharmacology Division, Department of Pharmacology, ISF College of Pharmacy, Moga, 142001, Punjab, India

    Rishabh Khera, Sidharth Mehan, Sumit Kumar, Pranshul Sethi, Sonalika Bhalla & Aradhana Prajapati

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Writing—original draft of the review, Rishabh Khera and Sumit Kumar; Conceptualization, Supervision, Sidharth Mehan; Writing review & editing, literature survey, Pranshul Sethi, Sonalika Bhalla, Aradhana Prajapati.

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Khera, R., Mehan, S., Kumar, S. et al. Role of JAK-STAT and PPAR-Gamma Signalling Modulators in the Prevention of Autism and Neurological Dysfunctions. Mol Neurobiol 59, 3888–3912 (2022). https://doi.org/10.1007/s12035-022-02819-1

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