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The Role of iPSC Modeling Toward Projection of Autophagy Pathway in Disease Pathogenesis: Leader or Follower

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Abstract

Autophagy is responsible for degradation of non-essential or damaged cellular constituents and damaged organelles. The autophagy pathway maintains efficient cellular metabolism and reduces cellular stress by removing additional and pathogenic components. Dysfunctional autophagy underlies several diseases. Thus, several research groups have worked toward elucidating key steps in this pathway. Autophagy can be studied by animal modeling, chemical modulators, and in vitro disease modeling with induced pluripotent stem cells (iPSC) as a loss-of-function platform. The introduction of iPSC technology, which has the capability to maintain the genetic background, has facilitated in vitro modeling of some diseases. Furthermore, iPSC technology can be used as a platform to study defective cellular and molecular pathways during development and unravel novel steps in signaling pathways of health and disease. Different studies have used iPSC technology to explore the role of autophagy in disease pathogenesis which could not have been addressed by animal modeling or chemical inducers/inhibitors. In this review, we discuss iPSC models of autophagy-associated disorders where the disease is caused due to mutations in autophagy-related genes. We classified this group as “primary autophagy induced defects (PAID)”. There are iPSC models of diseases in which the primary cause is not dysfunctional autophagy, but autophagy is impaired secondary to disease phenotypes. We call this group “secondary autophagy induced defects (SAID)” and discuss them.

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Abbreviations

5AdC:

5-aza-20-deoxycytidine

3-MA:

3-methyladenine

AD:

Alzheimer’s disease

ADPKD:

Autosomal dominant polycystic kidney disease

ALP:

Autophagy-lysosome pathway

ALS:

Amyotrophic lateral sclerosis

ANP:

Atrial natriuretic peptide

APP:

Amyloid-β precursor protein

ASM:

Acid sphingomyelinase

ATAD3A:

AAA-domain containing protein 3A

AVs:

Autophagic vacuoles

Aβ:

Amyloid beta

BCD:

Bietti’s crystalline dystrophy

BNP:

Brain natriuretic peptide

BVVL:

Brown-Vialetto-Van Laere syndrome

C9ORF72:

Chromosome 9 open reading frame 72

CCCP:

Carbonyl cyanide m-chlorophenyl hydrazone

CHMP2B:

Charged multivesicular body protein 2B

CM:

Cardiomyocyte

CMA:

Chaperone-mediated autophagy

CMT:

Charcot-Marie-Tooth

CYP4V2:

Cytochrome P450 family 4 subfamily V member 2

DA:

Dopaminergic neurons

DBA:

Diamond-Blackfan anemia

DCM:

Dilated cardiomyopathy

DHCR7:

7-dehydrocholesterol reductase

DRP1:

Dynamin-related protein 1

ER:

Endoplasmic reticulum

FAD:

Familial AD

FTD:

Frontotemporal dementia

GAA:

Acid alpha-glucosidase

GAGs:

Glycosaminoglycans

GBA:

beta-Glucocerebrosidase

GCase:

Glucocerebrosidase

GSDs:

Glycogen storage diseases

HPBCD:

2-hydroxypropyl-β-CD

HPGCD:

2-hydroxypropyl-γ-CD

Hsc70:

Heat shock cognate 71 kDa protein

HSCs:

Hematopoietic stem cells

HSP:

Hereditary spastic paraplegia

hESC:

Human embryonic stem cell

IDUA:

α-L-iduronidase

IP3:

Inositol three phosphate

JNCL:

Juvenile neuronal ceroid lipofuscinosis

LAMP-2:

Lysosomal-associated membrane protein type 2

LC3-II:

Light chain 3-II

LIMP-II:

Lysosomal integral membrane protein-2

LMNA:

Lamin A/C

LRRK2:

Leucine-rich repeat kinase 2

LSDs:

Lysosomal storage diseases

MAPT:

Microtubule-associated protein tau

MELAS:

Mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes

MIRO1:

Mitochondrial Rho GTPase 1

MN:

Motor neuron

MPS I:

Mucopolysaccharidoses type I

MSA:

Multiple system atrophy

mTOR:

Mammalian target of rapamycin

MFN2:

Mitofusin 2

MT-TL1:

Mitochondrial tRNALeu(UUR) gene

NPC:

Niemann-Pick disease type C

NPCs:

Neuronal precursor cells

NSCs:

Neural stem cells

NTG:

Normal tension glaucoma

OPTN:

Optineurin

PAID:

Primary autophagy induced defects

PARK7:

Protein deglycase DJ-1

PD:

Pompe disease

PINK1:

PTEN induced putative kinase 1

PKD:

Polycystin

POAG:

Primary open angle glaucoma

polyQ-AR:

Polyglutamine-expansion in androgen receptor

PRKN:

Parkin RBR E3 ubiquitin protein ligase

PSEN1:

Presenilin 1

RAN:

Repeat-associated non-ATG

rhGAA:

Recombinant human GAA

ROS:

Reactive oxygen species

RP:

Retinitis pigmentosa

RPE:

Retinal pigment epithelium

RyR2:

Ryanodine receptor type 2

SAID:

Secondary autophagy induced defect

SBMA:

Spinal and bulbar muscular atrophy

SCA3:

Spinocerebellar ataxia-3

SQSTM1:

Sequestosome 1

SLOS:

Smith-Lemli-Opitz syndrome

SMC:

Smooth muscle cell

SNCA:

Synuclein alpha

SOD1:

Superoxide dismutase

SPG11:

Spastic paraplegia 11

SQSTM1:

Sequestosome1

TBK1:

TANK binding kinase 1

TDP-43:

TAR DNA binding protein-43

TFEB:

Transcription factor EB

TPP1:

Tripeptidyl peptidase I

TREM2:

Triggering receptor expressed on myeloid cells 2

TRNT1:

tRNA nucleotidyl transferase, CCA-adding, 1

TSC2:

Tuberous sclerosis complex 2

UBQLN:

Ubiquilin

VCP:

Valosin-containing protein

VEGF:

Vascular endothelial growth factor

VSD:

Ventricular septal defect

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Acknowledgements

The author would like to thank Dr. Baharvand and Dr. Ghavami for their kind help and support. This study was supported by a grant from Royan Institute.

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Authors and Affiliations

  1. Department of Biology, School of Basic Sciences, Science and Research Branch, Islamic Azad University, Tehran, Iran

    Mina Kolahdouzmohammadi

  2. Department of Genetics, Reproductive Biomedicine Research Center, Royan Institute for Reproductive Biomedicine, ACECR, Tehran, Iran

    Mehdi Totonchi

  3. Department of Stem Cells and Developmental Biology, Cell Science Research Center, Royan Institute for Stem Cell Biology and Technology, ACECR, Banihashem Sq., Banihashem St., Resalat Highway, P.O. Box: 16635-148, Tehran, Iran

    Mina Kolahdouzmohammadi, Mehdi Totonchi & Sara Pahlavan

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  1. Mina Kolahdouzmohammadi
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Correspondence to Mehdi Totonchi or Sara Pahlavan.

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Kolahdouzmohammadi, M., Totonchi, M. & Pahlavan, S. The Role of iPSC Modeling Toward Projection of Autophagy Pathway in Disease Pathogenesis: Leader or Follower. Stem Cell Rev and Rep 17, 539–561 (2021). https://doi.org/10.1007/s12015-020-10077-8

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