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Genetic determinants of neuronal vulnerability to apoptosis

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Abstract

Apoptosis is a common mode of cell death that contributes to neuronal loss associated with neurodegeneration. Single-nucleotide polymorphisms (SNPs) in chromosomal DNA are contributing factors dictating natural susceptibility of humans to disease. Here, the most common SNPs affecting neuronal vulnerability to apoptosis are reviewed in the context of neurological disorders. Polymorphic variants in genes encoding apoptotic proteins, either from the extrinsic (FAS, TNF-α, CASP8) or the intrinsic (BAX, BCL2, CASP3, CASP9) pathways could be highly valuable in the diagnosis of neurodegenerative diseases and stroke. Interestingly, the Arg72Pro SNP in TP53, the gene encoding tumor suppressor p53, was recently revealed a biomarker of poor prognosis in stroke due to its ability to modulate neuronal apoptotic death. Search for new SNPs responsible for genetic variability to apoptosis will ensure the implementation of novel diagnostic and prognostic tools, as well as therapeutic strategies against neurological diseases.

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Abbreviations

AD:

Alzheimer’s disease

AIF:

Apoptosis-inducing factor

ALS:

Amyotrophic lateral sclerosis

Apaf-1:

Adaptor protein apoptotic peptidase-activating factor

APOE ε4:

Apolipoprotein E ε4

Bad:

Bcl-2-associated death promoter

Bak:

Bcl-2 antagonist/killer-1

Bax:

Bcl-2-associated X protein

Bcl-xL:

Bcl-2-like 1

Bcl-2:

B-cell lymphoma-2

BH:

Bcl-2 homology

Bid:

BH3-interacting domain death agonist

Bim:

Bcl-2-interacting mediator of cell death

CASP3:

Caspase-3

CASP8:

Caspase-8

CASP9:

Caspase-9

CNS:

Central nervous system

DISC:

Death-inducing signaling complex

FAF1:

Fas-associated protein 1

FasL:

Fas ligand

HDM2:

Human double minute-2

HLA:

Human leukocyte antigen

LRRK2:

Leucine-rich repeat kinase 2

Mcl-1:

Myeloid cell leukemia-1

MDM2:

Murine double minute-2

MS:

Multiple sclerosis

Noxa:

NADPH oxidase activator 1

OMM:

Outer mitochondrial membrane

PCD:

Programmed cell death

PD:

Parkinson disease

PUMA:

p53-upregulated modulator of apoptosis

SNP:

single-nucleotide polymorphisms

tBid:

Truncated Bid

Sp1:

Stimulatory protein 1

TNF:

Tumor necrosis factor

TRADD:

TNFR-associated death domain protein

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Acknowledgments

This work was supported by FEDER (European regional development fund), Instituto de Salud Carlos III (PS09/0366 and RD06/0026/1008) and Junta de Castilla y León (GREX206).

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  1. Instituto de Investigación Biomédica de Salamanca, Hospital Universitario de Salamanca, 37007, Salamanca, Spain

    Angeles Almeida

  2. Departamento de Bioquímica y Biología Molecular, Universidad de Salamanca, 37007, Salamanca, Spain

    Angeles Almeida

  3. Research Unit, University Hospital of Salamanca, Edificio Departamental (Lab. 122), Plaza Doctores de la Reina, 37007, Salamanca, Spain

    Angeles Almeida

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  1. Angeles Almeida
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Almeida, A. Genetic determinants of neuronal vulnerability to apoptosis. Cell. Mol. Life Sci. 70, 71–88 (2013). https://doi.org/10.1007/s00018-012-1029-y

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  • DOI: https://doi.org/10.1007/s00018-012-1029-y

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