Alarm protein sets off international interest

<http://www.sciencealert.com.au/index2.php

Wednesday, 14 November 2007 By Rhonda
Dredge La Trobe University microbiologist Professor Paul Fisher has
discovered that a faulty alarm at the cellular level could be
responsible for many rare and incurable conditions involving
mitochondria – the energy source contained within cells.
The State Government is so impressed by the implications of the La Trobe
research, carried out with PhD student Paul Bokko and others in
Professor Fisher's laboratory, that it has been selected as one of
five Victorian projects promoted in a recent biotechnology push into the
United States.

The Minister for Innovation, Mr John Brumby, announced details of the
new mitochondrial theory at BIO2007 – a biotechnology conference
attracting 19,000 delegates – in Boston in May.

His announcement coincided with scientific publication of the findings
in the international journal Molecular Biology of the Cell.

`Thanks to this research,' Mr Brumby said, `we now have a
completely new understanding of how mitochondrial disease is caused
– from a signalling disorder in the cells, rather than a fundamental
energy insufficiency as was previously thought.'

`The finding has important implications for the development of drug
therapies to treat the many different forms of mitochondrial disease, as
well as for most major neurodegenerative disorders.'

Professor Fisher's research has attracted substantial international
attention, including a piece in the London Financial Times, after the
findings were presented to journalists attending the World Science
Journalists Congress in Melbourne in April.

As a laboratory scientist who has dedicated the last fifteen years of
his life to research on signalling pathways in mitochondrially diseased
cells, Professor Fisher is grateful for the State Government's
support in promoting his work.

He has shown in the laboratory that an energy-sensing protein, known as
AMPK, is permanently activated in mitochondrially diseased cells. When
energy supplies drop, it begins signalling and interfering with other
signalling pathways, causing cell functions to shut down.

So far, Professor Fisher's work has used a type of amoeba called a
slime mould (the scientific name is Dictyostelium discoideum, Dicty to
its friends). Genetically inhibiting the production of the alarm protein
suppressed all of the `symptoms' of mitochondrial disease in
Dicty.

`If we can suppress the symptoms in humans as well, this research
may provide the first possibility of treating mitochondrial
diseases,' Professor Fisher said.

About 1,000 people at any one time suffer from genetic defects of the
mitochondria in Australia, resulting in a varied range of symptoms. More
than 50 children develop these conditions annually and more than half
die before adulthood.

All of the major neurodegenerative diseases such as
Alzheimer's, Huntington's and Parkinson's also involve
mitochondrial defects,' Professor Fisher said. `They might also
be turning on this alarm protein.' AMPK plays a `smoke
alarm' role to censor an impending energy crisis and to take
remedial action.

`If there is an energy problem, the cell does not want to embark on
division or processes that consume energy,' Professor Fisher said.
`So the protein switches them off before the situation becomes
critical.' In healthy cells, energy supplies return to normal, as
does cell functioning, but in diseased cells AMPK activity may trigger a
permanent shut-down.

`In these cases, AMPK acts like an oversensitive smoke alarm that
goes off every time you cook toast. Imagine if it locked every window
and door to stop the fire spreading and turned off the electricity and
gas. This is worse than the problem it tried to solve,' Professor
Fisher said.

Coincidentally, my neuro, whom I like because he actually enjoys dicussing research and honestly admits there is always something he could learn. He is matter of fact about not having as much time to stay completely up to date on internet activities, but has a stack of journals beside his desk to pull out references of what may come up in our discusssions - I don't think there has been one yet that I haven't seen somewhere else.

Anyway, the idea isn't to one up him and he knows that, I think. Now getting to the point. HE asked me if i have ever been evaluated for mitochondrial disease. I haven't and have questions.

Has anyone been tested specifically for mitochondrial disease? I believe there is a genetic mutation specific to it, or them, if there are many of these conditions. I know mitchondria is very significant in PD. but am just learning of separate mitochondria diseases.

Wow. That was an interesting article. I'm tempted to write to my consultant (in London) and ask how valid this is. Cos I suffer from mitochondrial cytopathy respiratory chain type I and IV - so I guess I was tested when I was little to be diagnosed. Definitely had muscle biopsy (and the scar to prove it). I don't know the scientific ins and outs though.

I find it difficult to understand the technicalities of medical research though I continue to try ! so please excuse my ignorance!
Any way : some few months after my diagnosis (15 months ago) I started experiencing lethargy and energy depletion which I understand to be common in pd patients. At that time, there were reports on possible role of creatine to protect brain cells by boosting the mitochondria which they call the power house of the cells.
I started taking creatine which (some how) seemed to solve my energy problem !!
I now take multivitamines, antioxidnats, NAC, lipuic acid, muccuna pruriens , creatine .. exercise for 2 hours with very cold showers .. NO proper pd drugs.. so far and i am not doing badly !
With my simplified knowledge .. I think pd has some thing to do with mitochondria !!!!!!!!!!!!!!!!!! I will greatly appreciate comments

The same is at work with CoQ10 is it not? I've always viewed CoQ10 as something that works in the early stages of PD, but I don't know if they have proven that it does anything for the advanced? Does anyone?

There's a case to be made [it probably has, lol] that energy is everything, no matter how you may "look" because of symptoms. IF one has the energy to take a shower and go grocery shopping, that's a good day

paula

The only way to know if you have a mitochondrial disease (please reread my post on Harley's post regarding what you would want the public to know) is to have a genetic test done. In the post I placed a link to Allinia Diagnostics who will help you know what genetic tests would be best for you.

If you go with a research program such as NINDS GENDIS you will not be allowed to know if your test is positive for abnormalities.

I have been posting this info for years but have been ignored because people see me as being a know it all. I am aggressive because I have a hard time being heard over all the stem cell debate.

I have continued to press this point home despite the angry responces I receive because, believe it or not , I care about all of you. Please don't just read the post. Check out the web site. I already know I have a mitochondrial disease and am in phase II study of a genetics program in the US.

Vicky

I knew you had a gene that defined your type of Parkinson's Vicky. I didn't know there were many types of mitochondrial diseases, probably because I am not a doctor and tend to focus on Parkinson's.

The rest of your judgemental assumptions are untrue and not worth reading. If it makes you feel any better shake you head and call me names at your computer.

paula

Ordinary folk like myself (zero knowledge in biology) make a simplifed (and often wrong) understanding of complicated research. So this is in few words my layman understanding.
The proper energy supply to the cells is vital to it's health and life. The mitochondria is the power house for cells. That is why "agents" enahancing the functions of the mitochondria like Creatine and Coq10 may be neuroprotective. These agents have the additional good effect of general energy boost for all persons with or without pd.
There may be a hundred reasons why some of us get pd and one of these reasons may be deficient energy to brain cells (or this may be a result of sick cells ? working in a vicious circle)
Dr. Fisher work outlines a mechanisim by which the cell over reacts to energy deficiency and worsen an allready bad situation. Any body to clarify/correct this simplified understanding.

In relation to the topic, I found this link : I really don't know how scientific !!?
http://www.restoreunity.org/increase...ax_muscles.htm
Parkinson's Disease is a form of accelerated aging. The shaking, the tremors, the cognitive decline, the imbalance of neurotransmitters, and many other conditions of Parkinson's, lead to declining efficiency and function in the body. Eventually declining efficiency and function result in degeneration, aging, disease, and breakdown. This leads to further decline in efficiency and function, which continues the cycle of declining health and further breakdown in the body. The great many problems of Parkinson's accelerate this entire process of declining efficiency and function.

Each particular problem of Parkinson's needs to be addressed and neutralized as a form of anti-aging. One of the major problems of Parkinson's is tremors and shakes. The muscle fiber is firing off unregulated and is out of control. There are several ideas to calm the nerves and the muscles.

The body needs sufficient energy in the form of ATP in order for muscle relaxation to occur. In Harper's Biochemistry, "if intracellular levels of ATP drop, ATP is not available to bind the S-1 head, actin does not disassociate and relaxation does not occur (Harper's Biochemistry, 25th Edition, Appleton & Lance, Stanford, Connecticut, 2000, Page 720.)" The body needs sufficient intracellular levels of ATP to help buffer some of the effects of the misfiring of muscle fiber in the forms of shakes and tremors. Without proper ATP levels, the muscles misfiring will not be able to relax.

ATP energy is produced inside cells at the sites called mitochondria. Mitochondria are the engines of the cells, producing energy in the form of ATP.

Dr. Bob was a MD internal medicine, orthomolecular doctor, MD psychiatrist, chiropractor, and healer 65 years. He was a diabetic who lived to 108 years with only 1 side effect 2 years before he passed away. Dr. Bob practiced a system of medicine called orthomolecular medicine.

The following ideas are orthomolecular methods to help relax muscle fiber and nerve stimulation. Orthomolecular medicine is a system of medicine that uses non-toxic, natural substances, in a wide range of dose, using mainly herbs and minerals/vitamins.

Dr. Bob's orthomolecular ideas:

1. Supplement a multivitamin and mineral. Dr. Bob recommended the brand Maxilife. All nutritional ideas need cofactors, which a multi provides.

2. Supplement a B-50, 3 times a day. B-1, B6, B3 and other B vitamins are involved in the production of energy in the mitochondria. The B vitamins start the energy process, they help control the buildup of waste products, they help regulate absorption into cell membranes, and other vital functions that help the mitochondria produce ATP.

3. Supplement CoQ10. CoQ10 supplies electrons in the energy cycle of the mitochondria. This is vital in producing ATP. There are different forms of CoQ10 and different potencies. The optimal dose has not yet been found in orthomolecular medicine, although 200-400 mg is a dose that is being considered by some doctors. CoQ10 probably has a toxic dose, so consult a nutritional expert such as an orthomolecular doctor, for the appropriate CoQ10 dose.

4. Supplement alpha lipoic acid 200 mg, 3 times a day. Alpha lipoic acid can help promote mitochondria cellular health, can help increase absorbability of nutrients important for the mitochondria, can help improve nerve conduction, which will help the mitochondria, and many other valuable functions of alpha lipoic acid at the mitochondria sites.

5. Supplement a total of 750 mg of no-flush hexanicotinate niacin, in divided doses, at the same time you use the B-50. Niacin is involved in increasing cell membrane permeability, which will help all the other nutrients.

6. Supplement ion-exchange whey protein concentrate. Whey supplies essential amino acids, building blocks of the body, and necessary to repair and rebuild muscle and nerves.

Additionally, in Harper's Biochemistry, "Calcium plays a key regulatory role," in the regulation of muscle contraction and relaxation. Proper levels of calcium are necessary to control muscle fiber. In the shaking type of tremors of Parkinson's, the nerve stimulation is erratic and can stimulate the parasympathetic and sympathetic nervous system. This can create intracellular imbalance, including unregulated calcium inside muscle cells.

The following orthomolecular ideas are to help promote proper calcium levels inside and outside cells, as well as reestablishing proper nerve conduction and nerve balance within cells.

1. Start at 1000 mg calcium supplementation a day, in divided doses. We recommend using calcium supplements that contain elemental calcium, the calcium found in your bones. Do not drink milk or eat chocolate around the time of calcium supplementation.

2. Start at 500 mg total magnesium supplementation each day. Supplement the calcium-magnesium at the same time, in a ratio of 2 parts calcium to 1 part magnesium.

3. Supplement vitamin B6 in the ratio of 3 parts magnesium to 1 part B6. Include the amounts of B6 in the B-50 and multivitamin and mineral.

4. Find your magnesium bowel tolerance. Most optimal amounts of supplements are not known. The body contains infinite wisdom. When you have too much magnesium, your body produces bowel movements to eliminate excess magnesium. Dr. Bob advised to supplement, ½ to 1-gram total of magnesium, each day. He recommended divided doses. He advised use optimal doses until bowel tolerance occurs (bowel movement immediately after using the supplement), afterwards use a dose slightly lower than bowel tolerance. For example, if you supplement magnesium in the AM and immediately afterwards have a bowel movement, then reduce your AM magnesium dose to slightly less than a dose that produces an immediate bowel movement. Do the same process with your magnesium dose in the PM. This is a basic guideline on finding an optimal magnesium dose, see an orthomolecular doctor or nutrition specialist before starting any of these ideas.

Special note - The stress of chronic disease often disrupts cellular balance, by increasing calcium inside cells. Supplementing calcium-magnesium in appropriate ratio helps to maintain cellular balance, by controlling parathyroid hormone (PTH). The parathyroid hormone (PTH) secretions maintain cellular balance by helping maintain appropriate levels of calcium in the bloodstream. "PTH secretion is inversely related to the ambient concentration of ionized calcium. Serum PTH declines in a rectilinear fashion in relation to serum calcium levels between 7.5 ml and 10.5 mg/dl. (Ref. Robert K. Murray, MD, Ph.D., Daryl K. Granmer, MD, Peter A. Mayes, Ph.D., D.Sc., Victor W. Fodwell, Ph.D., Harper's Biochemistry, twenty-fifth edition. Appleton & Lance, Stanford, Connecticut, 2000, page 570.)" This means levels of calcium in the bloodstream regulate PTH. The amount of PTH in the bloodstream helps regulate normal extra cellular fluid calcium. Magnesium is a cofactor in this cell regulation process.

Include all the above supplements at the same time. The misfiring of muscle fiber possibly indicates improper levels of calcium inside cells and depletion of ATP. The above orthomolecular methods can help balance calcium levels and help produce ATP.

Dr. Bob note - Many nutritional protocols involving the mitochondria include supplementing L-carnitine or acetyl-L-carnitine. L-carnitine can help transport fat to the mitochondria to be burned as energy, which is usually recommended to improve mitochondria function. However, in orthomolecular medicine, L-carnitine supplementation is a method also used to regenerate nerve velocity. Dr. Bob advised to be careful that supplementing L-carnitine does not lead to increasing shakes and tremors in Parkinson's. If you supplement L-carnitine and you have Parkinson's, observe carefully if your tremors and shakes increase. Perhaps in beginning stages of Parkinson's L-carnitine may not result in increased shakes and tremors. Dr. Bob advised to be cautious about acetyl-L-carnitine supplementation for Parkinson's.

Dr. Bob also included other orthomolecular methods to calm muscle fiber and nerves. His basic idea was to increase Vo2 Max. This would help maintain proper pH levels at the muscle fiber. From Harper's Biochemistry, "Fatigue of muscles during exercise is a phenomenon that almost everyone has experienced. What is the cause? The primary cause is accumulation in muscle tissue not of lactate (due to anaerobic glycolysis), but rather of protons. Increase of protons (decreased pH) can affect the function of muscles in a number of ways (page 733)." There will be other articles about Parkinson's on this web site describing ways to buffer the muscle cells to help maintain proper pH. Proper pH is a method that can help regulate muscle fiber and calm muscle cells.

In conclusion, there are many conditions of pathology associated with Parkinson's. There is no magic bullet to the many conditions that can occur. Each problem must be neutralized and balanced, to help slow down the accelerated aging of Parkinson's.


Note – In order for these anti-aging ideas to be successful, you must use supplements of the highest quality. Dr. Bob often said, "almost all supplement companies produce poor quality." You can consider the product page of this web site. Almost all the products met Dr. Bob’s approval. Since he passed away we have attempted to keep the same high standards.

WARNING: DO NOT STOP ANY TREATMENT OR MEDICATION YOU CURRENTLY USE. CONSULT WITH YOUR DOCTOR BEFORE STARTING THE USE OF SUPPLEMENTS.

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The Food and Drug Administration has not evaluated any of the statements contained on this web site. The information contained in this article is not intended to diagnose, treat, cure or prevent any disease. Remember each person's body is different and will react differently to various herbal, vitamin and mineral supplements. Therefore, any supplementation must be administered on an individual basis. Use the information found on this web site as precisely that: Information. You and your doctor must make any final decisions. This information is not meant to replace any doctor and patient consultation. This information should in no way replace your personal physician's advice.

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