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Dysregulation of IGF-1/GLP-1 signaling in the progression of ALS: potential target activators and influences on neurological dysfunctions

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Abstract

The prominent causes for motor neuron diseases like ALS are demyelination, immune dysregulation, and neuroinflammation. Numerous research studies indicate that the downregulation of IGF-1 and GLP-1 signaling pathways plays a significant role in the progression of ALS pathogenesis and other neurological disorders. In the current review, we discussed the dysregulation of IGF-1/GLP-1 signaling in neurodegenerative manifestations of ALS like a genetic anomaly, oligodendrocyte degradation, demyelination, glial overactivation, immune deregulation, and neuroexcitation. In addition, the current review reveals the IGF-1 and GLP-1 activators based on the premise that the restoration of abnormal IGF-1/GLP-1 signaling could result in neuroprotection and neurotrophic effects for the clinical-pathological presentation of ALS and other brain diseases. Thus, the potential benefits of IGF-1/GLP-1 signal upregulation in the development of disease-modifying therapeutic strategies may prevent ALS and associated neurocomplications.

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Data Availability

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Abbreviations

AAV:

adeno-associated virus

AD:

Alzheimer’s disease

Akt:

protein kinase B

ALS:

amyotrophic lateral sclerosis

ALS2:

alsin rho guanine nucleotide exchange factor

AMPA:

α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid

ANG:

angiogenin

APAF-1:

apoptotic protease activating factor 1

APE1:

apurinic/apyrimidinic endonuclease 1

APP:

amyloid precursor protein

ATP:

adenosine triphosphate

BBB:

blood-brain barrier

bFGF:

basic fibroblast growth factor

BV-2:

cellosaurus cell line BV-2

C9orf72:

C9 open reading frame 72

cAMP:

cyclic AMP

CBT:

corticobulbar tract

CD4+:

cluster of differentiation 4

CD8+:

cluster of differentiation 8

CGN:

cerebellar granule cells

ChAT:

choline acetyl transferase

CK:

cytokine

CNS:

central nervous system

CREB:

cAMP-response element-binding protein

CST:

corticospinal tract

DAMP:

damage-associated molecular pattern

DNA:

deoxyribonucleic acid

EAE :

experimental autoimmune encephalomyelitis

ERK:

extracellular signal-regulated kinase

FAK1:

focal adhesion kinase 1

fALS:

familial ALS

FOXO3:

forkhead box O3

FUS:

fused in sarcoma

GCL:

granule cell layer

GDNF:

glial-derived neurotrophic factor

GLP:

glucagon-like peptide-1

GLP-1R:

glucagon-like peptide-1 receptor

GSK-3β:

glycogen synthase kinase-3β

HD:

Huntington’s disease

HNE:

4-hydroxy-2-nonenal

HSP:

heat shock proteins

HUVEC:

human umbilical vein endothelial cells

IGF-1:

insulin-like growth factor-1

IGF-1R:

insulin-like growth factor-1 receptor

IGF-2:

insulin-like growth factor-2

IGFBP-1:

insulin-like growth factor binding protein-1

IL:

interleukin

iNOS:

inducible nitric oxide synthase

LMN:

lower motor neuron

LPS:

lipopolysaccharide

LTB4:

leukotriene B4

MAG:

myelin-associated glycoprotein

MOG:

myelin oligodendrocyte glycoprotein

MBP:

myelin basic protein

MDC:

monodansylcadaverine

mHtt:

mutant Huntingtin protein

MND:

motor neuron disease

MPTP:

1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine

MS:

multiple sclerosis

MSC:

mesenchymal stromal cells

mTOR:

mammalian target of Rapamycin

NDD:

neurodegenerative disorders

NF-κB:

nuclear factor kappa light chain enhancer of activated B cells

NMDA:

N-methyl D-aspartate

NO:

nitric oxide

NR2B:

N-methyl D-aspartate receptor subtype 2B

3-NT:

3-nitrotyrosine

3-oxoG:

8-oxo-deoxyguanosine

ODC:

oligodendrocyte cells

OPC:

oligodendrocyte progenitor cells

OS:

oxidative stress

PARP-1:

poly ADP ribose polymerase-1

PC12:

pheochromocytoma cell 12

PD:

Parkinson’s disease

PDK1:

3-phosphoinositide-dependent protein kinase 1

PEG:

polyethylene glycol

PGE:

prostaglandin E

PI3K:

phosphoinositide 3-kinase

PKA:

protein kinase A

PLP:

pyridoxal phosphate

Pro-OL:

pro-oligodendroblast

PS1:

presenilin 1

RCT:

randomized controlled trial

rhIGF-1:

recombinant human IGF-1

RNS:

reactive nitrogen species

ROS:

reactive oxygen species

sALS:

sporadic ALS

siRNA:

small interference RNA

SN:

substantia nigra

SOD:

superoxide dismutase 1

Src kinase:

proto-oncogene tyrosine-protein kinase

TARDBP:

TAR DNA-binding protein

TDP-43:

Tar DNA-binding protein 43

TEM:

transmission electron microscopy

Th1:

T helper cell type 1

TLR-4:

toll-like receptor-4

TNF-α:

tumor necrosis factor-α

TNF-R1:

tumor necrosis factor receptor 1

Treg:

regulatory T cells

UMN:

upper motor neuron

VAPB:

vesicle-associated membrane protein-associated protein B

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Acknowledgements

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

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

    Ambika Shandilya & Sidharth Mehan

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AS (Ambika Shandilya) involved in investigation, writing - original draft, review writing; SM (Sidharth Mehan) has contributed towards conceptualization, resource gathering, supervision, writing - review and critical editions. All authors read and approved the manuscript and all data were generated in-house and that no paper mill was used.

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Shandilya, A., Mehan, S. Dysregulation of IGF-1/GLP-1 signaling in the progression of ALS: potential target activators and influences on neurological dysfunctions. Neurol Sci 42, 3145–3166 (2021). https://doi.org/10.1007/s10072-021-05328-6

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