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Does any drug to treat cancer target mTOR and iron hemostasis in neurodegenerative disorders?

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Abstract

The prevalence of neurodegenerative disorders such as Alzheimer’s disease, Parkinson’s disease and Huntington’s disease are increased by age. Alleviation of their symptoms and protection of normal neurons against degeneration are the main aspects of the research to establish novel therapeutic strategies. Iron as the one of most important cation not only play important role in the structure of electron transport chain proteins but also has pivotal duties in cellular activities. But disruption in iron hemostasis can make it toxin to neurons which causes lipid peroxidation, DNA damage and etc. In patients with Alzheimer and Parkinson misbalancing in iron homeostasis accelerate neurodegeneration and cause neuroinflmmation. mTOR as the common signaling pathway between cancer and neurodegenerative disorders controls iron uptake and it is in active form in both diseases. Anti-cancer drugs which target mTOR causes iron deficiency and dual effects of mTOR inhibitors can candidate them as a therapeutic strategy to alleviate neurodegeneration/inflammation because of iron overloading.

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Abbreviations

4EBP1:

4E binding protein1

6-OHDA:

6-hydroxydopamine

Aβ:

Amyloid beta

AD:

Alzheimer’s disease

AICD:

APP intracellular domain

APP:

Amyloid precursor protein

APPsβ:

Ectodomain of APP

Atg7:

5 autophagy related gene 7.5

Atg13:

Autophagy related gene 13

BACE:

Beta secretase

BBB:

Blood brain barrier

βCTF or C99:

APP carboxy-terminal fragment

CNS:

Central nervous system

Depto:

DEP domain–containing mTOR-interacting protein

DMT1:

Divalent metal transporter 1

eIF2α:

Eukaryotic initiation factor 2α

eIF4E:

Eukaryotic initiation factor 4 epsilon

ETC:

Electron transport chain

FPN1:

Ferroportin 1

FRDA:

Friedreich ataxia

HIF-1:

Hypoxia inducible factor 1

IL-1β:

Interleukin 1β

iNOS:

Inducible nitric oxide synthase

IRE:

Iron responsive elements

IRPs:

Iron regulatory proteins

LRRK2:

Leucine-rich repeat kinase 2

MFRN1/2:

Mitoferrins 1/2

MPTP:

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

mLSTR8:

Mammalian lethal with sec-18 protein 8

mPTP:

Mitochondrial permeability transition pore

mtDNA:

Mitochondrial DNA

Mtf:

Mitochondrial ferritin

mTOR:

Mammalian target of rapamycin

NFTs:

Neurofibrillary tangles

NM:

Neuromelanin

NO:

Nitric oxide

NOS:

Nitric oxide synthase

NOX:

NADPH oxidase

NTBI:

Non-transferrin bound iron

·OH:

Hydroxyl radical

·ONOO:

Peroxynitrite radical

PA:

Phosphatidic acid

PD:

Parkinson’s disease

PKCα:

Protein kinase C alpha

PS1:

Presenilin-1

ROS:

Reactive oxygen species

SNP:

Single nucleotide polymorphism

SNpc:

Substantia nigra pars compacta

STEAP 1–4:

Six-transmembrane epithelial antigen of prostate 1–4

TfR:

Transferrin receptor

TNFα:

Tumor necrose factor α

ULK1:

Unc like kinase 1

UTR:

Untranslated region

V-ATPase:

Vacuolar H+-ATPase

VDAC:

Voltage dependent anion channels

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  1. Department of Biology, New Mexico State University, Las Cruces, NM, 88003, USA

    Mohammad Jodeiri Farshbaf

  2. Department of Biology, School of Sciences, University of Isfahan, Isfahan, Iran

    Kamran Ghaedi

  3. Department of Cellular Biotechnology, Cell Science Research Center, Royan Institute for Biotechnology, ACECR, Isfahan, Iran

    Kamran Ghaedi

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Jodeiri Farshbaf, M., Ghaedi, K. Does any drug to treat cancer target mTOR and iron hemostasis in neurodegenerative disorders?. Biometals 30, 1–16 (2017). https://doi.org/10.1007/s10534-016-9981-x

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