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Autophagy and apoptosis cascade: which is more prominent in neuronal death?

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Abstract

Autophagy and apoptosis are two crucial self-destructive processes that maintain cellular homeostasis, which are characterized by their morphology and regulated through signal transduction mechanisms. These pathways determine the fate of cellular organelle and protein involved in human health and disease such as neurodegeneration, cancer, and cardiovascular disease. Cell death pathways share common molecular mechanisms, such as mitochondrial dysfunction, oxidative stress, calcium ion concentration, reactive oxygen species, and endoplasmic reticulum stress. Some key signaling molecules such as p53 and VEGF mediated angiogenic pathway exhibit cellular and molecular responses resulting in the triggering of apoptotic and autophagic pathways. Herein, based on previous studies, we describe the intricate relation between cell death pathways through their common genes and the role of various stress-causing agents. Further, extensive research on autophagy and apoptotic machinery excavates the implementation of selective biomarkers, for instance, mTOR, Bcl-2, BH3 family members, caspases, AMPK, PI3K/Akt/GSK3β, and p38/JNK/MAPK, in the pathogenesis and progression of neurodegenerative diseases. This molecular phenomenon will lead to the discovery of possible therapeutic biomolecules as a pharmacological intervention that are involved in the modulation of apoptosis and autophagy pathways. Moreover, we describe the potential role of micro-RNAs, long non-coding RNAs, and biomolecules as therapeutic agents that regulate cell death machinery to treat neurodegenerative diseases.

Graphical abstract

Mounting evidence demonstrated that under stress conditions, such as calcium efflux, endoplasmic reticulum stress, the ubiquitin–proteasome system, and oxidative stress intermediate molecules, namely p53 and VEGF, activate and cause cell death. Further, activation of p53 and VEGF cause alteration in gene expression and dysregulated signaling pathways through the involvement of signaling molecules, namely mTOR, Bcl-2, BH3, AMPK, MAPK, JNK, and PI3K/Akt, and caspases. Alteration in gene expression and signaling cascades cause neurotoxicity and misfolded protein aggregates, which are characteristics features of neurodegenerative diseases. Excessive neurotoxicity and misfolded protein aggregates lead to neuronal cell death by activating death pathways like autophagy and apoptosis. However, autophagy has a dual role in the apoptosis pathways, i.e., activation and inhibition of the apoptosis signaling. Further, micro-RNAs and LncRNAs act as pharmacological regulators of autophagy and apoptosis cascade, whereas, natural compounds and chemical compounds act as pharmacological inhibitors that rescue neuronal cell death through inhibition of apoptosis and autophagic cell death.

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Abbreviations

NDD’s:

Neurodegenerative diseases

AD:

Alzheimer’s disease

PD:

Parkinson’s disease

ALS:

Amyotrophic lateral sclerosis

HD:

Huntington’s disease

MS:

Multiple sclerosis

UPR:

Unfolded protein response

miRNA:

Micro RNAs

ULK:

UN51-like Ser/Thr kinases

Atg13:

Autophagy-related protein 13

PI3K:

Phosphatidylinositol-3-kinase

Vps34:

Vacuolar protein sorting 34

VPS15:

P15

Atg6:

Beclin-1

Atg14:

Barkor

LC3:

Light chain 3

SNAREs:

Soluble NSF attachment protein receptor

PCD:

Programmed cell death

Bcl-2:

B-cell lymphoma 2

TNF:

Tumor necrosis factor

FADD:

Fas-associated death domain protein

TRAIL:

TNF-related apoptosis-inducing ligand

BH3:

Bcl-2 homology region 3

Smac/DIABLO:

Second Mitochondria-derived Activator of Caspases/ Direct IAP-Binding protein with Low PI

AIFs:

Apoptosis-inducing factors

BAX:

Bcl-2 associated X protein

BAK:

Bcl-2 homologous antagonist/killer

IAP:

Inhibitor of apoptosis

XIAP:

X-linked inhibitor of apoptosis

ROS:

Reactive oxygen species

NOS:

Nitrogen oxygen species

JAK/STAT:

Janus kinases/ Signal Transducer and Activator of Transcription proteins

NF-κB:

Nuclear factor kappa-light-chain-enhancer of activated B cells

RIPK1:

Receptor interacting protein kinase 1

RIPK3:

Receptor interacting protein kinase 3

DAMP’s:

Damage-associated molecular patterns

MLKL:

Mixed lineage kinase domain-like

TRADD:

Tumor necrosis factor receptor type 1-associated DEATH domain protein

TRAF2:

TNF receptor associated factor 2

Akt:

Protein kinase B

ERAD:

Endoplasmic-reticulum-associated protein degradation

PKR:

Protein kinase RNA

PERK:

Protein kinase RNA like ER kinase

IRE1α:

Inositol-requiring protein 1α

ATF6:

Activating transcription factor 6

CHOP/GADD153:

X-linked inhibitor of apoptosis protein and co-operating with C/EBP homologous protein

ASK1:

Apoptosis signal regulating kinase 1

JNK:

Jun N-terminal kinase

PKC:

Protein kinase C

PUMA:

P53 upregulated modulator of apoptosis

NOXA:

Phorbol-12-myristate-13-acetate-induced protein 1

TPEN:

N,N,N′,N′-tetrakis(2-pyridylmethyl) ethylenediamine

PARP:

Poly (ADP-ribose) polymerase-1

AMPK:

5' AMP-activated protein kinase

m-TORC1:

Mammalian target of rapamycin complex 1

DRAM:

Damaged regulated autophagy modulator

TFEB/TFE3:

The transcription factor EB/Transcription Factor Binding to IGHM Enhancer 3

FOXO3a:

Transcription factor forkhead box O3a

VEGF:

Vascular endothelial growth factor

VEGF2:

Vascular endothelial growth factor receptor 2

STAT3:

Signal transducer and activator of transcription 3

Aβ:

β-Amyloid

MPP+ :

1-Methyl-4-phenylpyridinium ion

FLICE:

FADD-like IL-1β-converting enzyme

BBC3:

Bcl-2 Binding Component 3

HMGB1:

High mobility group box 1

DRGNs:

Dorsal root ganglial neurons

RHEB:

Ras homolog enriched in brain

MAPK:

Mitogen activated protein kinase

Mcl-1:

Myeloid leukemia cell differentiation protein

Hrk/DP5:

Activator of apoptosis Harakiri/ death protein 5

MPTP+ :

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

Cdk5:

Cyclin dependent kinase 5

MEK/ERK:

Mitogen-activated protein kinase 1

ERK1/2:

Extracellular signal-regulated kinase 1

CREB:

CAMP-response element-binding protein

GAPDH:

Glyceraldehyde 3-phosphate dehydrogenase

APAF1:

Apoptotic protease activating factor 1

NLRP3:

NLR family pyrin domain containing 3

PYCARD:

PYD and CARD domain containing

iNOS:

Inducible nitric oxide synthase

AICAR:

5-Aminoimidazole-4-carboxamide ribonucleotide

GSK3:

Glycogen synthase kinase 3

GSK3β:

Glycogen synthase kinase 3 β

GSK3α:

Glycogen synthase kinase 3 α

NMDAR:

N-methyl-D-aspartate receptor

Nrf2:

Nuclear factor erythroid 2-related factor 2

NLRP1:

NACHT-LRR-PYD domains-containing protein 1

NLRP3:

NACHT-LRR-PYD domains-containing protein 3

NLRC4:

NLR Family CARD Domain Containing 4

ALR’s:

Augmenter of liver regeneration

PAMP and DAMP:

Pathogen and damage associated molecular patterns

SNpc:

Substantia nigra pars compacta

PBBI:

Penetrating ballistic-like brain injury

ROF:

Roflupram

CNS:

Central nervous system

ER:

Endoplasmic reticulum

MALAT1:

Metastasis-associated lung adenocarcinoma transcript 1

NEAT2:

Nuclear-enriched transcript 2

CRNDE:

Colorectal neoplasia differentially expressed

GFAP:

Glial fibrillary acidic protein

BrdU:

Bromodeoxyuridine

SNHG12:

Small nucleolar host gene 12

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Acknowledgements

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

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Authors and Affiliations

  1. Molecular Neuroscience and Functional Genomics Laboratory, Department of Biotechnology, Mechanical Engineering Building, Delhi Technological University (Formerly Delhi College of Engineering), Room# FW4TF3, Shahbad Daulatpur, Bawana Road, Delhi, 110042, India

    Rohan Gupta, Rashmi K. Ambasta &  Pravir Kumar

  2. Delhi, India

    Pravir Kumar

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  1. Rohan Gupta
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  2. Rashmi K. Ambasta
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  3. Pravir Kumar
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RG, RK and PK conceived and designed this project. Data collected and analyzed by RG and RK. Art work is done by RG and PK. Manuscript has been written by RG and PK.

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Correspondence to Pravir Kumar.

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Gupta, R., Ambasta, R.K. & Pravir Kumar Autophagy and apoptosis cascade: which is more prominent in neuronal death?. Cell. Mol. Life Sci. 78, 8001–8047 (2021). https://doi.org/10.1007/s00018-021-04004-4

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