MANF: What Is It And How To Increase Mesencephalic Astrocyte-Derived Neurotrophic Factor

 
 

Mesencephalic Astrocyte-Derived Neurotrophic Factor

Mesencephalic astrocyte-derived neurotrophic factor (MANF; also known as ARMET or arginine-rich mutated in early stages of tumor) belongs to the fourth family of neurotrophic factors. R

It plays a huge role in repairing neurons and cells after oxidative stress, and has promising uses for the future in neurodegenerative diseases (such as Parkinson's Disease). R

Contents:

  1. Basics Of MANF
  2. Benefits And Roles In The Body
  3. How To Increase MANF
  4. Caveats
  5. Mechanism of Action
  6. More Research

Basics Of MANF

MANF was first discovered in the brains of rats, but later found to be in humans as well. R

MANF is a neurotrophic factor (like BDNF, NGF, GDNFCNTF and CDNF) which is a protein the brain uses to grow larger and work more efficiently.

It is also a cardiomyokine, which are heart-derived secreted proteins that affect cardiovascular function. R

MANF is widely expressed in the nervous system and non-neuronal tissue, such as the hypothalamus, cerebral cortex, hippocampus, cerebellum, caudate nucleus, liver, and heart, as well as the eyes, blood, saliva, bones, cartilage, testis, spleen, and pancreas. R R R R R

It may be highly expressed during the developmental stages of the brain. R

Dysregulation of MANF may cause:

  • Oxidative Stress (ie overall stress in the body/cells) R
  • Dopamine neuron destruction (dopamine depletion) R
  • Neuroinflammation (ie Alzheimer's) R
  • Increased risk of injury in low oxygen conditions (ie hypoxia, stroke, heart attack) R R
  • Diabetes R
  • Kidney Disease R

Benefits And Roles In The Body

1. Protects The Body Against Oxidative Stess

MANF is regulated by oxidative stress in the endoplasmic reticulum (ER) and golgi. R R

The ER is responsible for folding proteins in the cell and keeping the cell stable (regulating the unfolded protein response, UPR). R

Damage to the ER (AKA endoplasmic reticulum stress, ERS) is a common pathology to many chronic illnesses including hypoxia, stroke, insulin resistance, neuroinflammation, and vision problems. R R R R R R R R

MANF not only modifies ER homeostasis to protect cells against ERS-induced cell death, but also regulates neuroinflammation and the immune response to promote tissue repair and regeneration. R R

MANF protects the survival of cells by its ability to inhibit autophagy (via AMPK/mTOR pathway). R R

Also, by slowing down the cell death pathway (via inhibition of Bax), MANF can protect mitochondria from death. R

2. Protects The Brain

 
nerve-cell-2213009_1280.jpg
 

MANF can protect the brain against the damaging effects of alcohol. R

It can rescue neurons in the brain against toxin-induced damage. R

In the cerebellum, MANF may help with Spinocerebellar ataxia (SCA). R

3. Improves Parkinson's Disease

MANF (similarly to VEGF) can potently protect and restore dopamine neurons in the brain. R R R

For example, MANF can protect dopamine neurons and alleviate Parkinson's Disease (PD)-like symptoms in animal models exposed to the toxin 6-hydroxydopamine (6-OHDA, a toxin that destroys dopamine neurons in the substantia nigra). R R

By regulating ERS, MANF improves motor function more efficiently than other neurotrophic factors. R

MANF's effects improving PD are even more effective when combined with CDNF or GDNF. R R R R

4. Improves Stroke And Seizure Outcome

MANF can protect the body against hypoxia-induced injury (injury from lack of oxygen) and loss of glucose to the brain. R R

This is one way MANF can protect the brain against damage during stroke. R R R

For example, in animal models that were given MANF after stroke, had less brain damage (smaller infarct size) and a longer survival rate vs controls. R

In another animal study of stroke, MANF was able to improve motor activity and increased body symmetry during movement. R

MANF is slightly upregulated after seizures, and its expression may protect the brain during epilepsy. R

5. Protects The Eyes

 
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5423635/

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5423635/

 

By protecting cells (ie glia and retinal cells) against hypoxia-induced damage and regulating ERS, MANF may help with glaucoma, diabetic retinopathy, retinitis pigmentosa, and age-related macular degeneration (AMD). R R R R R

MANF can also promote tissue repair and successful regeneration in the retina. R 

6. Plays A Role In Diabetes

 
http://www.cell.com/cell-reports/abstract/S2211-1247(14)00201-0

http://www.cell.com/cell-reports/abstract/S2211-1247(14)00201-0

 

MANF is very important for prevention of diabetes. R

MANF is highly expressed in pancreatic beta cells and protects them from ERS. R

MANF may also enhance growth of new beta-cells. R

MANF deficiency results in pancreatic beta-cell depletion and diabetes in mice. R

MANF is increased in the serum in children with type 1 diabetes. R

This increase in MANF is inversely correlated with C-peptide levels (which is an indirect measure of functional beta-cell mass), but not associated with diabetes-predictive autoantibodies. R

MANF is also increased in newly diagnosed prediabetic and diabetic patients. R

7. Plays A Role Kidney Function

MANF may help predict kidney disease. R

For example, high levels of MANF found in urine of animal of Nephrotic Syndrome (NS). R

8. Protects The Heart

MANF can protect the heart from loss of oxygen. R R

It may protect the heart from enlargement and during heart failure may reduce the size of the damage. R 

9. Plays A Role In Autoimmunity

MANF mRNA is dramatically upregulated in peripheral white blood cells from patients with autoimmune inflammatory disease, including rheumatoid arthritis (RA) and systemic lupus erythematosus (SLE). R

10. Regulates Eating

 
cooking-1013455_960_720.jpg
 

MANF, like many other proteins, helps regulate feeding and hunger via regulation of the hypothalamus.R

MANF may help improve eating as in animal models MANF overexpression leads to hyperphagia (excessive eating), while underexpression of MANF leads to hypophagia (reduced eating). R

MANF may also help with increasing body weight. R

MANF may also protect the cells against nutrient depletion. R

How To Increase MANF

Diet/Lifestyle:

Anything that causes oxidative stress to the endoplasmic reticulum should theoretically increase MANF, so hormesis may be effective as well. R

  • Alcohol (not recommended as it is an adaptive response) R
  • Fasting R R
  • Having a circadian rhythm? (the supraoptic nucleus (SON) and tuberomammillary nucleus (TMN) in the hypothalamus exhibit particularly high levels of MANF expression. The cell bodies in the SON produces anti-diuretic hormone (ADH) while the neurons in TMN release histamine and is involved with the control of arousal, sleep and circadian rhythm.) R 
  • Grape Seed (in cows) R
  • Heat (via heat shock proteins - Sauna) R R
  • Hypoxia (use a mask)R
  • Inflammation (upregulation of MANF is an adaptive response under inflammatory condition) R
  • Neurotoxins (such as estrogenics) R
  • UV Exposure (such as sun exposure) R
  • Venom (from Cotesia chilonis) R

Drugs/Chemicals:

  • Lactacystin R
  • Tamoxifen R
  • Thapsigargin R
  • Tunicamycin R
  • Valproic Acid (low amounts increase, high amounts decrease MANFR R

Pathways:

  • AP-1 R
  • ATF6 R
  • Nogo-A (possibly, via Reticulons) R
  • SP-1 R
  • UPR R
  • VGF R
  • XBP1 R

Caveats

Overexpression of MANF (in the hypothalamus) may contribute to insulin resistance (IR) in the brain. R

Increasing MANF level in the hypothalamus leads to an impaired insulin response, which results in hyperphagia and obesity. R

Mutations in MANF (ARP gene) have been indicated in lung, breast, prostate, pancreatic, and head/neck cancer. R R

Although by slowing down the cell cycle, MANF may help prevent cancer by its ability to cancer cell replication and division. R

Mechanism Of Action

 
https://link.springer.com/article/10.1007%2Fs10072-017-3042-2

https://link.springer.com/article/10.1007%2Fs10072-017-3042-2

 

Simple:

  • Increases GRP78 R
  • Increases mTOR R R
  • Reduces Akt R
  • Reduces AMPK R R
  • Reduces Bax R
  • Reduces C-Peptide R
  • Reduces Caspase-3 R
  • Reduces CHOP R
  • Reduces HSP70 R
  • Reduces IFN-γ R
  • Reduces IL-1β R
  • Reduces NF-κB R R
  • Reduces p65 R
  • Reduces TNF-α R

Advanced:

  • Uniquely, MANF (also known as Arginine-rich protein,ARP) has two mechanisms of action: first, MANF is secreted into extracellular space, and addition of MANF protein protects specific types of neurons both in vitro and in vivo. R R
  • Unlike GDNF, CDNF and MANF have a C-terminally located ER retention signal and therefore a significant amount of these proteins are retained in the ER after translation. R R R
  • ER stress enhances not only expression but also secretion of MANF. R R
  • MANF is a negative inhibitor of inflammation (via NF-kb): inflammation causes MANF to relocalize to the nuclei, which then MANF interacts with the DNA binding domain of p65 through its C-terminal SAP-like domain in the nuclei under the condition of inflammation or ER stress. R
  • MANF is retained in the ER by KDELR via the C-terminal RTDL sequence, and by calcium dependent interaction with GRP78. R
  • The N-terminus of MANF can bind membrane and free lipids. R
  • MANF may also protect against endotoxemia (the presence of endotoxins in the blood) by inhibiting toll-like receptors (TLR) activation and response to lipopolysaccharides (LPS), thus reducing IL-1beta, TNF-alpha, and IFN-gamma. R R
  • In microglia MANF activation promotes a phenotype switch of macrophages from pro-inflammatory (M1) to anti-inflammatory (M2). R
  • MANF protects against Bax-mediated cell death, thus also protecting mitochondria from death. R R
  • MANF transgenic mice were less sensitive to the food intake regulation mediated by insulin (via PIP4k2b). R
  • MANF can recruit PIP4k2b into the ER, where PIP4k2b becomes active and reduces the activation of AKT downstream of insulin pathway. R

More Research

  • The closest structural homologs for CDNF and MANF N-terminal domain are saposin-like proteins (SAPLIPs) granulysin and NK-lysin, which function as defense proteins against bacterial cells and are able to disrupt target cell membranes. R
  • DOCK/MANF may have possible relation to Lupus via mutation in MANF. R