For leaky
ATP, Popeye might want to try Dexpramipexole and
Suramin,
or even the already approved Mirapex
If you
are old enough to be a parent, you will have encountered problems with some kind
of leak. A leaky roof, a leaky pipe, a leaky
washing machine, an air-conditioning unit... The list goes on, the older you get.
I have been
preoccupied by fixing a leak recently.
We have a large roof terrace and, in the winter, water started leaking from
the ceiling in the floor below. I
improvised a system to catch all the water, but still I had to find the source
of the leak.
I did
finally find the source of the problem and most importantly without digging up
95% of the terrace. Now I have to put the
5% back together again.
Leaks are
often extremely difficult to locate, because water always finds the easiest
path and the dripping you see might have originated from a leak far away. Nobody wants to fix leaks, because it can be a
pretty thankless task and you can cause plenty of damage in the process,
without solving the problem. So, as with
fixing autism, I ended up doing much of the fixing myself. The damage had actually been there since the
house was built, hidden under ceramic tiles.
I recently
read about leaky ATP in Fragile-X, where ATP leaks from the mitochondria into
the cell.
This fits
neatly into Professor Naviaux’s belief that ATP is leaking from the cell into
the extracellular space, as the basis for his concept of the cell danger
response, as a unifying and treatable feature of most autism.
Sounds
complicated?
Just think
of it as bunch of leaks you need to fix.
ATP has many functions:-
·
It
is the fuel your cells need to function.
·
It
is a signalling molecule within a cell and importantly between different cells.
·
It
is used to make your DNA
Mitochondria
The ATP –
ADP Cycle
You can think
of ATP as a fully charged battery. Once
the energy has been used up the flat battery is called ADP and it goes back for
recharging in the mitochondria. It is a
continuous cycle.
ADP is powered
back to ATP through the process of releasing the chemical energy available in
food; this is constantly performed via aerobic respiration in
the mitochondria. This process is
also called OXPHOS and has been covered in previous posts. In most mitochondrial disease the problem is
that one of the four mitochondrial enzyme complexes is insufficient; this means
that the ATP-ADP cycle is restricted.
There is then insufficient energy to power the brain in times of peak
energy requirement. This can cause loss
of myelination and ultimately cell death.
ATP in
Fragile X
It looks
like in Fragile X the mitochondria in the brain do not work properly. ATP is
leaking from the mitochondria and this stops synapses from maturing.
A synapse is
just the junction between one neuron and its neighbour.
The immature
synapse manifests as autistic behavior.
When you plug the leak with Dexpramipexole, a drug trialed for ALS and now
asthma, dendritic spines mature and autistic behavior is reduced.
To
what extent this leakage occurs in idiopathic autism is unknown, but we know
that impaired dendritic spine formation/morphology is a key feature of most
autism and that it can be modified, although the sooner you start the better
the result will be.
It
looks to me that some people diagnosed with mitochondrial disease based on
blood tests may actually have leaking ATP which then affects metabolic pathways
and shows up with odd blood test results, that is then misdiagnosed as mitochondrial
disease. Note that many people diagnosed
with mitochondrial disease show no response to therapy.
In
Professor Naviaux’s theory, the ATP leak is from the cell membrane, like the
outer wall of the cell. He thinks that
ATP is leaking and this then sends a false danger signal to the rest of your
brain. This is his Cell Danger Response
(CDR). Because the brain thinks it is
under attack it is set in a permanent pro-inflammatory state, this gets in the
way of basic functions the developing brain needs to complete. This might explain why the microglia (the
brain’s immune cells) are found to be permanently activated in autism; this
then means that they do not carry out their regular brain housekeeping activities
very well, like pruning synapses.
Naviaux
wants to plug the leaks in the cell wall using Suramin, which is an old
anti-parasite drug made by Bayer, the giant German company.
The
link between the Fragile X research from Yale and Naviaux’s work at UCSD is
that ATP needs to be kept in the right place for the brain to function
correctly.
Leaky
ATP will cause you big problems.
Now for the supporting
research
Leaky ATP
in Fragile X
Fragile X syndrome traits may stem from leaky
mitochondria
The persistent leak influences which metabolic pathway the cell uses to generate energy, the team discovered by using a technique called mass spectrometry. For example, fragile X neurons produce more enzymes associated with glycolysis — a pathway commonly used by immature cells — than do typical neurons. Previous studies have shown altered mitochondrial metabolism in people with other forms of autism2.
Adding dexpramipexole to the cells of fragile X mice decreased production
of lactate dehydrogenase and other enzymes linked to glycolysis, suggesting
that closing the leak causes the neurons to start to use different, more mature
metabolic pathways.
Giving injections of dexpramipexole to fragile X model
mice lessened their hyperactivity, repetitive behaviors and excessive grooming
— traits that are reminiscent of those seen in people with autism and in those
with fragile X syndrome. Mice that received the dexpramipexole injections also
had neurons with more mature dendritic spines and decreased levels of protein
synthesis.
Dexpramipexole has been tested in people with the
neurological disease amyotrophic lateral sclerosis and found safe, but it is
unclear how it would affect young people if taken over sustained periods of
time.
ATP Synthase c-Subunit Leak Causes Aberrant Cellular Metabolism
in Fragile X Syndrome
Loss of the gene (Fmr1) encoding Fragile X mental retardation protein (FMRP) causes increased mRNA translation and aberrant synaptic development. We find neurons of the Fmr1-/y mouse have a mitochondrial inner membrane leak contributing to a "leak metabolism." In human Fragile X syndrome (FXS) fibroblasts and in Fmr1-/y mouse neurons, closure of the ATP synthase leak channel by mild depletion of its c-subunit or pharmacological inhibition normalizes stimulus-induced and constitutive mRNA translation rate, decreases lactate and key glycolytic and tricarboxylic acid (TCA) cycle enzyme levels, and triggers synapse maturation. FMRP regulates leak closure in wild-type (WT), but not FX synapses, by stimulus-dependent ATP synthase β subunit translation; this increases the ratio of ATP synthase enzyme to its c-subunit, enhancing ATP production efficiency and synaptic growth. In contrast, in FXS, inability to close developmental c-subunit leak prevents stimulus-dependent synaptic maturation. Therefore, ATP synthase c-subunit leak closure encourages development and attenuates autistic behaviors.
Highlights
·
ATP
synthase c-subunit leak in Fragile X causes aberrant metabolism
·
Changes
in ATP synthase component stoichiometry regulate protein synthesis rate
·
Inhibition of the leak normalizes
synaptic spine morphology and Fragile X behavior
In Brief
Lack of FMRP in Fragile X neurons is associated with a leak
in the ATP synthase, the blockade of which normalizes cellular and behavioral
disease phenotypes.
Now they fix the
leak using Dexpramipexole (Dex) and cyclosporine A (CsA)
We have found that the mitochondrial inner membrane leak of
FX neurons and cells is caused by abnormal levels of ATP synthase c-subunit.
The c-subunit leak causes persistence of a mitochondrial leak metabolic
phenotype characterized by high glycolytic flux, high lactate levels, and
increased levels of glycolytic and TCA enzymes. The leak also aberrantly
elevates overall and specific protein synthesis; a decrease in c-subunit level
or pharmacological inhibition of the ATP synthase leak reduces protein synthesis
rates and decreases the levels of leak metabolism enzymes. In Fmr1/y synapses,
stimulation-dependent protein synthesis is absent. This is correlated with a
lack of stimulus induced EF2 phosphorylation and a lack of synthesis of the ATP
synthase b-subunit. These abnormalities are readily reversed by ATP synthase
leak inhibitors, suggesting that leak closure is required for the ATP-dependent
phosphorylation of EF2 adjacent to mitochondria. EF2 phosphorylation may
regulate the change in subsets of proteins synthesized and may be correlated
with- the overabundant synthesis of enzymes supporting a high flux
glycolytic/TCA cycle ‘‘leak’’ metabolism indicative of metabolic immaturity.
Consistent with the hypothesis that the c-subunit leak is also a major cause of
synapse immaturity, we find that inhibition of the ATP synthase leak allows the
maturation of synapses and normalizes autistic behaviors.
Closing Leaky Mitochondria Halts Behavioral Problems in Fragile X, Study Suggests
“In Fragile X neurons,
the synapses fail to mature during development. The synapses remain in an
immature state and this seems to be related to their immature metabolism,” she
said.
The investigators tested
whether closing the leak to boost the efficiency of ATP production would lessen
behavioral abnormalities.
They first saw that nerve cells treated with an ATP
synthase inhibitor named dexpramipexole (Dex) — a form of the common
Parkinson’s therapy Mirapex ER
(pramipexole) and previously tested as a treatment for amyotrophic lateral sclerosis — increased
the levels of ATP.
Two-day treatment with Dex also reversed autistic-like
behaviors, namely excessive time
spent grooming and compulsive shredding of the animals’ nests. The treatment
also reduced hyperactivate behaviors.
“We find that inhibition
of the ATP synthase leak allows for the maturation of synapses and normalizes
autistic behaviors in a mouse model of [fragile X],” the team wrote.
Jonas and her team now
intend to further test the effectiveness of this and other leak-closing
therapies for improving learning.
The lab is conducting a study assessing the role of leaky
membranes in memory formation. Findings could pave the way for novel
therapeutics for fragile X and autism, as well as for Alzheimer’s disease.
Dr Naviaux
and Suramin for Autism
I have
covered Suramin in previous posts. There
is a presentation below by Prof Naviaux that is for lay people, it is good to
hear directly from the man himself.
Autism Treatment, the cell danger response and the SAT1 trial
In essence
he says that when cells are stressed, they leak ATP and this creates the cell
danger response. If you have suramin in
your bloodstream, it plugs the ATP channels and stops it leaking out of the
cell and so blocks the cell danger response.
It is the cell danger response that is causing the symptoms we see as autism.
Conclusion
Who to call to fix an ATP leak?
If it is a case of Fragile X, there looks to be potential solution,
but you will definitely not find it at your local doctor’s office.
For a
mouse with Fragile X, you might choose Dexpramipexole. Dexpramipexole was developed as a therapy for
ALS (motor neuron disease), but failed in phase 3 trials and is now being developed
for asthma.
For a
human, the logical place to start would be the already approved Mirapex, which is
currently used to treat Parkinson's disease
and restless legs syndrome.
Clearly somebody should make a clinical trial of the existing
drug.
I expect what will happen is that the Yale researchers will
come up will a new drug that can be patented as a novel therapy for Fragile X. This way they get to make some money, but a decade
is wasted.
Is leaky ATP from mitochondria an issue in broader autism,
beyond Fragile X? That is still unknown, but the Yale researchers seem to think their work has potential application in both autism and Alzheimer’s.
In the case of broader autism, Dr Naviaux and his partner
Kuzani have some competition from Paxmedica.
Both groups seek to monetize Dr Naviaux’s published research.
It looks like the German giant Bayer does not want to help
either group. Instead of just tapping
into Bayer’s existing production of Suramin, Kuzani and Paxmedica will have to
figure out how to produce Suramin.
This all helps us to understand why there still are no approved
therapies for core Autism or indeed Fragile X and yet there is a mountain of
research. Too many barriers and
interests to overcome.
If you want to fix leaky ATP any time soon, you will be doing
it mainly by yourself. This has been my experience
with most other kinds of leak!
