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Potential Role of MANF, an ER Stress Responsive Neurotrophic Factor, in Protecting Against Alcohol Neurotoxicity

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Abstract

Alcohol exposure during pregnancy is harmful to the fetus and causes a wide range of long-lasting physiological and neurocognitive impairments, collectively referred to as fetal alcohol spectrum disorders (FASD). The neurobehavioral deficits observed in FASD result from structural and functional damages in the brain, with neurodegeneration being the most destructive consequence. Currently, there are no therapies for FASD. It is exigent to delineate the underlying mechanisms of alcohol neurotoxicity and develop an effective strategy of treatment. ER stress, caused by the accumulation of unfolded/misfolded proteins in the ER, is the hallmark of many neurodegenerative diseases, including alcohol-induced neurodegeneration. Mesencephalic astrocyte-derived neurotrophic factor (MANF) is a newly discovered endoplasmic reticulum (ER) stress responsive neurotrophic factor that regulates diverse neuronal functions. This review summarizes the recent findings revealing the effects of MANF on the CNS and its protective role against neurodegeneration. Particularly, we focus the role of MANF on alcohol-induced ER stress and neurodegeneration and discuss the therapeutic potential of MANF in treating alcohol neurotoxicity such as FASD.

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Abbreviations

FASD:

Fetal alcohol spectrum disorders

FAS:

Fetal alcohol syndrome

PAE:

Prenatal alcohol exposure

ER:

Endoplasmic reticulum

SER:

Smooth endoplasmic reticulum

CNS:

Central nervous system

MANF:

Mesencephalic astrocyte-derived neurotrophic factor

CDNF:

Cerebral dopamine neurotrophic factor

NTFs:

Neurotrophic factors

BDNF:

Brain-derived neurotrophic factor

GFLs:

Glial cell line-derived neurotrophic factor family of ligands

GDNF:

Glial cell line-derived neurotrophic factor

CNTF:

Ciliary neurotrophic factor

IL-6:

Interleukin 6

ROS:

Reactive oxygen species

UPR:

Unfolded protein response

PERK:

Pancreatic ER kinase-like ER kinase

IRE1α:

Inositol-requiring enzyme 1 α

ATF6:

Activating transcription factor 6

XBP1s:

X-box binding protein 1

GRP78:

Glucose-regulated protein 78 kDa

ERAD:

ER-associated protein degradation

PD:

Parkinson’s disease

AD:

Alzheimer’s disease

ARP:

Arginine-rich protein

UTR:

Untranslated region

SAPLIP:

Saposin-like protein

PDIs:

Protein disulfide isomerases

SCG:

Superior cervical ganglion

KDELRs:

KDEL receptors

TH:

Tyrosine hydroxylase

KO:

Knock-out

NSCs:

Neural stem cells

MCAO:

Middle cerebral artery occlusion

ERSE:

ER stress response element

AAV:

Adeno-associated virus

BMSC:

Bone marrow mesenchymal stem cells

6-OHDA:

6-Hydroxydopamine

HSP70:

Heat shock protein 70

Aβ:

Amyloid β-peptide

APP/PS1:

Amyloid precursor protein/presenilin 1

ITGC:

Inferior temporal gyrus of the cortex

SCA17:

Spinocerebellar ataxia 17

TBP:

TATA box binding protein

RP:

Retinitis pigmentosa

sI/R:

Simulated ischemia/reperfusion

MRI:

Magnetic resonance imaging

GD:

Gestation days

PD:

Postnatal days

ADH:

Alcohol dehydrogenase

CYP2E1:

Cytochrome P450 2E1

ALDH:

Aldehyde dehydrogenase

BAC:

Blood alcohol concentration

BBB:

Blood-brain barrier

4-PBA:

4-Phenylbutyric acid

MEFs:

Mouse embryonic fibroblasts

Bcl2:

Bcl2 apoptosis regulator

Bcl2l1:

Bcl2 like 1

Bax:

Bcl2 associated X apoptosis regulator

Bak1:

Bcl2 antagonist/killer 1

Bad:

Bcl2 associated agonist of cell death

Bid:

BH3 interacting domain death agonist

Bnip3:

Bcl2 interacting protein 3

cHAP:

Crossed high alcohol preferring

SERCA:

Sarco/endoplasmic reticulum Ca2+

ATP:

Adenosine tri-phosphate

ADP:

Adenosine di-phosphate

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Acknowledgements

We thank Cody Dvorak for proofreading the manuscript.

Funding

This work was supported by the National Institutes of Health (NIH) grants AA017226 and AA015407. It was also supported in part by the Department of Veterans Affairs, Veterans Health Administration, Office of Research and Development [Biomedical Laboratory Research and Development: Merit Review (BX001721)].

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Authors and Affiliations

  1. Department of Pathology, University of Iowa Carver College of Medicine, Iowa City, IA, 52242, USA

    Wen Wen, Hui Li & Jia Luo

  2. Iowa City VA Health Care System, Iowa City, IA, 52246, USA

    Jia Luo

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  1. Wen Wen
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  2. Hui Li
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  3. Jia Luo
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W. W. reviewed literatures, wrote the manuscript, and made the tables and figures; H. L. revised the manuscript; and J. L. revised the manuscript and provided financial support. All authors approved the final version of the manuscript.

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Correspondence to Jia Luo.

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Wen, W., Li, H. & Luo, J. Potential Role of MANF, an ER Stress Responsive Neurotrophic Factor, in Protecting Against Alcohol Neurotoxicity. Mol Neurobiol 59, 2992–3015 (2022). https://doi.org/10.1007/s12035-022-02786-7

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