Source: https://autism.fratnow.com/blog/folate-transport-systems-i-transmembrane-carriers/
Two
readers of this blog have been telling me about the fundamental role of brain
energy and metabolism in autism. Marco sent me a book called Brain Energy by a
psychiatrist at the Harvard Medical School. He stumbled upon this subject when
he encouraged a patient to lose weight using the ketogenic diet. As well as
losing weight, the patient’s decades-long psychiatric disorders seemed to
vanish. The author, Dr Palmer, now believes that many of his patients actually
have metabolic disorders as the underlying basis of their psychiatric
symptoms.
Our
reader Natasa is approaching with a similar idea, essentially that autism
features a brain running on empty.
Today’s
post is about increasing the level of folate within the brain, by targeting
similar metabolic pathways to those that will boost “brain energy.”
Low
levels of folate within the brain will cause varying degrees of neurological
disorder.
There
are three ways folate can cross into the brain.
1.
Folate
receptor alpha (FRA)
2. Proton-coupled folate
transporter (PCFT)
3. Reduced folate carrier (RFC)
Autoantibodies
to the FRA have been linked to neurodevelopmental diseases, particularly
cerebral folate deficiency, schizophrenia and autism. Recent
studies have shown that these neurodevelopmental disorders can be treated with
folinic acid (leucovorin).
Dr Frye,
Professor Ramaekers and others are
targeting the problem of low folate in the brain by supercharging the level of
folate in the bloodstream and hoping more squeezes through the blood brain
barrier.
In my
previous post I mentioned that Agnieszka has pointed out the idea of using the
supplement PQQ. This targets the third transport mechanism above, it is aiming
to get more folate across via the Reduced
Folate Carrier (RFC).
Somebody recently wrote their PhD thesis on exactly this topic:-
Camille Alam, Department of Pharmaceutical Sciences, University of Toronto
Additionally, we provided in vitro and in vivo evidence that RFC expression and transport activity is inducible by another transcription factor, NRF-1. These findings demonstrate that augmenting RFC functional expression through interaction with specific transcription factors could constitute a novel strategy for enhancing brain folate delivery. Modulating folate uptake at the BBB may have clinical significance due to the lack of established optimal therapy for neurometabolic disorders caused by loss of FRα or PCFT function.
What
Camille is saying is that if folate transport mechanism number 1 and/or number
2 are not working, we can reinvigorate mechanism number 3.
So if
you have Dr Frye’s folate receptor antibodies, or PCFT isn’t working then you might focus on Reduced Folate Carrier (RFC).
The good
news is that we have lots of ways to target Reduced Folate Carrier (RFC).
We do
not, it seems, have any clever ways to target PCFT.
NRF-1
and PGC1-alpha
There is
a lot in this blog about PGC1-alpha, because it is the master regulator for
biogenesis of mitochondria.
All
those people with impaired “brain energy” would love to activate PGC1-alpha.
NRF-1 is
an activator of mitochondrial respiratory chain genes. NRF-1 specifically
targets genes encoding subunits of the mitochondrial respiratory chain
complexes, particularly complexes I, III, and IV. By binding to their
promoters, NRF-1 directly stimulates their transcription, leading to increased
synthesis of these critical protein components and enhanced oxidative
phosphorylation (OXPHOS) capacity.
Synergy
between NRF-1 and PGC-1alpha
PGC-1alpha
acts as the upstream regulator. Various stimuli, such as exercise, cold
exposure, and certain hormones, can trigger PGC-1alpha expression. Once
activated, PGC-1alpha directly interacts with and co-activates NRF-1, enhancing
its binding to target gene promoters and amplifying its transcriptional
activity.
NRF-1 as
the downstream effector. NRF-1
fine-tunes the expression of specific mitochondrial genes, ensuring a balanced
and efficient OXPHOS system. This synergy between PGC-1alpha and NRF-1
optimizes mitochondrial function and cellular energy production.
So for
Natasa, trying to boost energy production in the brain and in the rest of the
body, it would be ideal to have more NRF-1 and more PGC-1alpha
What has
optimized mitochondrial function got to do with more folate in the brain?
It turns
out that you can increase expression of Reduced Folate Carrier (RFC) via
activating NRF-1 and/or PGC1alpha.
So what
is good for your brain energy is likely to also be good for your brain folate.
Folates are important for neurodevelopment and cognitive function. Folate transport across biological membranes is mediated by three major pathways: folate receptor alpha (FRα), proton-coupled folate transporter (PCFT), and reduced folate carrier (RFC). Brain folate transport primarily occurs at the choroid plexus through FRα and PCFT; inactivation of these transport systems results in suboptimal folate levels in the cerebrospinal fluid (CSF) causing childhood neurological disorders. Our group has reported that upregulation of RFC at the blood-brain barrier (BBB) through interactions with specific transcription factors, that is, vitamin D receptor (VDR) could increase brain folate delivery. This study investigates the role of nuclear respiratory factor 1 (NRF-1) in the regulation of RFC at the BBB. Activation of NRF-1/PGC-1α signaling through treatment with its specific ligand, pyrroloquinoline quinone (PQQ), significantly induced RFC expression and transport activity in hCMEC/D3 cells. In contrast, transfection with NRF-1 or PGC-1α targeting siRNA downregulated RFC functional expression in the same cell system. Applying chromatin immunoprecipitation (ChIP) assay, we further demonstrated that PQQ treatment increased NRF-1 binding to putative NRF-1 binding sites within the SLC19A1 promoter, which encodes for RFC. Additionally, in vivo treatment of wild type mice with PQQ-induced RFC expression in isolated mouse brain capillaries. Together, these findings demonstrate that NRF-1/PGC-1α activation by PQQ upregulates RFC functional expression at the BBB and could potentially enhance brain folate uptake.
The hugely simple intervention mentioned above is to just take vitamin D. This has nothing to do with brain energy.
Folates are critical for brain development and function. Abnormalities in brain folate transport have been implicated in a number of childhood neurodevelopmental disorders, including cerebral folate deficiency syndrome, hereditary folate malabsorption, and autism spectrum disorders. These disorders have devastating effects in young children, and current therapeutic approaches are not sufficiently effective. In this study, we demonstrate that functional expression of the folate transporter, reduced folate carrier, at the blood–brain barrier and its upregulation by the vitamin D nuclear receptor can remarkably increase folate transport to the brain. These findings provide a strategy for enhancing brain folate delivery for the treatment of neurometabolic disorders caused by folate transport defects.
Taking
vitamin D has become popular in recent years.
A
correlation does not guarantee causality.
It was thought that vitamin D might be the silver bullet to improved
health in older people. It has not proved to be.
Low
vitamin D also correlates with less time outdoors, doing some physical
activity. Taking vitamin D does not mean you will live longer, but we know for
sure that exercise improves many medical concerns that will improve healthy
life expectancy.
The
concern many people now have regarding skin cancer leads to some healthy active
people having low vitamin D. Put on that sunscreen and your exposed skin will
not be able to produce your vitamin D.
Vitamin
D is important to health and is easy to maintain in the normal range, but it is
just one element of good health. It might be one way to increase folate in the brain, for those who need it.
Conclusion
How do
you increase folate in the brain?
The
obvious way is to put more folate in your blood, this is the standard therapy.
You either take calcium folinate tablets or, very rarely, the more potent infusions.
If you have antibodies blocking transport via FRA, you could follow the hypothesis that these antibodies are from a reaction to cow’s milk and try going dairy-free. There is a complex relationship between milk and folate receptor alpha antibodies (FRAA), but direct evidence of milk causing FRAA production is limited.
Milk, particularly cow's milk, contains proteins similar to folate receptor alpha found in humans. Some individuals, mainly those with a genetic predisposition, could develop FRAA that cross-react with these milk proteins. This cross-reactivity would not necessarily mean the milk directly caused FRAA production but might trigger an existing immune response. Some studies, though not all, have found an association between higher milk consumption and increased FRAA levels.
If you
want to increase folate transport via our third mechanism, Reduced Folate
Carrier (RFC) you have many options:
The
obvious first step is to take a vitamin D supplement to raise levels to the
high end of normal. This can be done by taking a larger supplement just once a
week, because vitamin D has a long half-life.
As you
can see from the study below in children there is a correlation between low
vitamin D and low folate in children.
Evaluation of correlation between vitamin D with vitamin B12 and folate in children
The present study reported a positive correlation between vitamin D and
vitamin B12 and folate levels. Regular measurement of these two micronutrient
levels in children with vitamin D deficiency is important for public health.
Vitamin
D is low in much of the population, even more so in wintertime. It seems
particularly low in children with autism, perhaps because they are spending
less time playing outside than other children.
Activate
NRF-1 and/or PGC1alpha:
1. Exercise,
particularly endurance
training
2. PQQ
supplement
3. Perhaps
resveratrol/pterostilbene
4. Butyric
acid / sodium butyrate
5. The very
safe old drug Metformin
6. Other
type 2 diabetes drugs like Pioglitazone
Metformin
has been shown to raise IQ in Fragile-X by about 10 points and has a range of
metabolic benefits and even cancer preventative effects. This common diabetes
medication primarily targets AMPK, an energy sensor molecule upstream of
PGC-1alpha. By activating AMPK, metformin indirectly stimulates PGC-1alpha and
subsequently NRF1, leading to enhanced mitochondrial function.
Pioglitazone
has been researched in autism and is my choice for peak risk spring/summer
aggression and self-injury. Pioglitazone can potentially upregulate PGC-1alpha
expression through several pathways:
•
Pioglitazone activates AMPK, an important energy
sensor molecule. AMPK can then stimulate PGC-1alpha expression through various
signaling pathways.
•
Pioglitazone activates PPAR-gamma and PPAR-gamma
directly interacts with PGC-1alpha, potentially increasing its activity.
I think
Metformin has a better safety profile than Pioglitazone and so better for every day use.
Butyric
acid does have the potential to activate PGC-1alpha. Butyric acid is produced in
the gut by fermentation. You need “good” bacteria and fiber. People with
healthy diet naturally produce it. You can also buy it as a supplement (sodium
butyrate) since it has numerous benefits – everything from gut health, bone
health to a tight blood brain barrier.
According
to a doctor I was talking to recently, nobody wants to hear that exercise is a
key part of health. It is free and the side effects are generally all good
ones. Endurance exercise will boost NRF1 and PGC1alpha. Many people with autism
are overweight, often due to the psychiatric drugs they have been put on.
Sirtuin activators
boost NRF1 and PGC1 alpha. There are drugs and foods which can do this, but a potent
way is through exercise.
I hope
Dr Frye is checking his patients’ vitamin D levels and supplementing to the
safe upper limit.
Those
taking I/V calcium folinate might want to look at the more potent ways to
activate NRF1 and/or PGC1alpha.