A simplified chronological model for the pathogenesis of Parkinson’s Disease

This is work in progress.

I propose a theoretical model linking oxidative stress, mitochondrial dysfunction and the degeneration of axons of dopaminergic neurons in the striatum. These axons have reduced capacity to combat mitochondrial dysfunction due their very long supply lines from the nucleus. As a result they suffer energy loss due to mitochondrial dysfunction which causes retrograde degeneration and Parkinson’s disease.

Please download the model as a Pdf file on the documents page.

Parkinson’s disease is characterized by the loss of dopaminergic neurons in the substantia nigra (SN) in the midbrain and a deficit of dopamine in the terminal synapses in the striatum, but a simple model presenting the stages leading up to this condition has so far not been presented.

This article proposes a simplified model that schematically represents the chronology of the major events believed to be involved in the pathogenesis of Parkinson’s disease in a way designed to be accessible to patients. The model also proposes which steps may be subject to influence through medical or patient intervention, so that patients can make informed decisions about how to manage their own condition. The model covers the progression of Parkinson’s disease from benign redox imbalance in brain cells to chronic oxidative stress which initiates a cascade of two major events: (i) mitochondrial dysfunction, a condition which reduces the energy available to host cells and (ii) degeneration of vulnerable axons in the striatum region of SN neurons as a consequence of this energy loss. The model links these major events and draws attention to the considerable delays occurring between the beginning of the events and the observation of symptoms eventually produced by them, a situation which masks the true progression of the disease.

To build this model, evidence for the three major conditions already identified in the progression of Parkinson’s disease; age-related oxidative stress, mitochondrial damage and loss of dopaminergic SN neurons was investigated. There are convincing arguments for the processes that link these conditions and make up the basic version of the model. Each process has also been examined in more detail to consider the potential roles other factors having the capacity to modify or invalidate the primary model, such as α-synuclein, genetic variants, toxins or lifestyle. These additional factors add complexity to the model but help to understand how the pathogenesis and development of Parkinson’s disease is multifactorial. This article presents the simplified model only. The more complex model will be presented at a later date.

What were you told when you were first diagnosed with Parkinson’s disease?

I was diagnosed with Parkinson’s disease in 2018, but had many of its symptoms years before that. The first was loss of the sense of smell, but the symptoms that most affected my quality of life came in the 5 years before diagnosis: fatigue, daytime sleepiness, poor sleep, apathy, bad moods, confusion, urinary urgency, constipation, sensitivity to heat or cold and leg pain. All of these symptoms were initially attributed to something else. Apathy, sleepiness (laziness) and bad moods were personality problems, so my own fault. Urinary urgency was a prostate problem. Constipation was due to bad diet. Fatigue was just getting old…

The expert opinion changed with my first visible movement problems. My left leg was dragging behind and my left hand started trembling. I became stiff and slow. In 2018, my neurologist said I had Parkinson’s disease and many of the symptoms I had endured over the last 5 years were now attributable to Parkinson’s disease! Strange how expert opinion can change. At this point you might be tempted to ask your doctor: – “What can you do to control this disease?

– “Well, your brain cells that produce a neurotransmitter called dopamine have been dying off for years. You may have already lost up to 70% of these neurons”.
– “70% lost, like, well … lost at sea ? You mean dead, Doctor?
– “Yes, it’s a neurodegenerative disease and you will lose more each year.

And what causes these brain cells to die?
“The cause is unknown…” your Doctor may reply. “and there is currently no therapy to slow or stop it progressing.

Look it up on the internet. All the big Parkinson’s web sites say the same thing.
It’s all so simple and logical. It’s not the Doctor’s fault. Just bad luck really.

Your doctor may have prescribed some pills to help replace some of the lost dopamine. They will help with the symptoms, well, some of them, for a while.
“Your next appointment will be in 6 months, have a nice day”.

What your Doctor really meant is that he or she doesn’t know and cannot be bothered to look into the possible causes” and since there is no approved therapy”to slow progression, you are on your own.

So let’s just think about this for a moment. We started out with about 400,000 dopamine-producing neurons, so we have already lost about 280,000 which leaves about 120,000 still alive. If this is right, Parkinson’s disease is just a lottery. It’s like losing pennies through a hole in your pocket. You didn’t notice it happening and now you’re nearly broke.

Now, Dear Parkinson’s disease experts, with all due respect, “Do you really expect us to swallow that?”

The Patient Researcher is not an expert in Parkinson’s disease, but for many years he was an expert in another field of science. His very first task, as a research student, was to question established knowledge from a previous era, still printed in the best text books. It didn’t seem right, like the sun going round the Earth, but there wasn’t an obvious alternative. It was an enigma waiting to be solved.

It took him 2 years of measurements, calculations and creative thought to solve that enigma before an elegant solution was published in “Nature”. That solution then became the model for new established knowledge. It is often cited to this day, although the present interpretation is even more elegant. So, one of the first lessons I learned as a young scientist was to question what the experts say. And it doesn’t matter who the expert is, myself included. If the established wisdom doesn’t stand up to logical analysis, then whatever the experts say, it is probably wrong.

So, now think about the Parkinson’s neuron number’s game above. Does it add up? No, but it’s a great way to avoid the next question:
“What is the alternative explanation?”

If it were simply a game of declining numbers of neurons over time, wouldn’t that simply lead to a regular decline in health over the years without all these highs and lows, good days and bad days that Parkinson’s patients fear so much? Why would sleep, diet, stress or exercise make any difference?

“Could an alternative explanation be that neurons somehow get sick or damaged long before they die? Wouldn’t that be more reasonable? And if that were the case, maybe some of the 70% “lost” neurons might still be alive but simply too sick to function properly? Wouldn’t that make more sense?”

As their host ages, neurons, unlike many other cells, are not regularly renewed, but also grow old. Neurons carry with them the scars of a lifetime of service”.

A quick look at the research going on to understand neurodegenerative diseases reveals many possible causes. One that stands out above the others is that neurons are constantly being damaged by aggressive chemicals produced as by-products of cellular function, because the system that should normally eliminate them is not working properly. These chemicals are called free radicals and Reactive Oxygen Species (ROS) or Reactive Nitrogen Species (RNS). They are highly aggressive oxidants… just like like bleach! The system that is failing to eliminate them uses a process that activates gene expression which produces antioxidants right inside the cells. In neurons of people with Parkinson’s disease, this system, which I call the Redox Balance System (RBS) is no longer working properly. The ROS and RNS then cause oxidative stress which damages various cell components, especially mitochondria. This causes inflammation and eventually cell death.

Can we do anything to reduce this oxidative stress or repair the system that should normally take care of it? Well not officially, remember there is “no approved therapy.” However, many researchers agree that there are ways to repair the Redox Balance System and so slow down the progression of PD. They also know which type of medication is likely to be effective. One of the most promising substances is called sulforaphane, an isothiocyanate that can easily be made from broccoli seeds or sprouts. It has been tested in laboratories and on animal models of Parkinson’s disease and has been shown to be effective, but has not been clinically trialled on humans with Parkinson’s disease, so it remains “not approved”.

In the last 3 months of 2020, a small number of pioneering Parkinson’s patients decided to test whether sulforaphane would do the job. They purchased their own seeds and equipment and followed the same method to make and ingest a broccoli seed tea containing sulforaphane and record their PD symptoms. The results of this self-supervised test showed very clearly that their non-motor symptoms were strongly reduced in just 6 weeks, whereas their motor symptoms remained almost unchanged. Remember that non-motor symptoms of Parkinson’s disease are those that other people do not see, like fatigue, sleep problems and urinary incontinence.

So what happened? Does this suggest that some dysfunctional neurons were beginning to function better? “Perhaps they were not all dead after all?”

Now, the beneficial properties of sulforaphane have been known for more than 10 years, but it remains “not approved” and is unlikely to get approval because it is very cheap to make and cannot be patented. Maybe it’s about time for Parkinson’s patients to get angry and question what the experts are telling them.

You can read more about this in other posts and documents on this site.

The broccoli seed tea experiment

The results of eight coordinated (n=1) studies, designed and executed entirely by People with Parkinson’s, reveal that non-motor symptoms were strongly attenuated by a broccoli seed tea, whereas motor symptoms remained unchanged over the 6-week program.

For a complete report of the results and their interpretation please download the article entitled “Broccoli tea experiment results and interpretation” on the “Documents” page.

These results imply that the mechanisms involved in generating and attenuating non-motor symptoms differ from those for motor symptoms. They are fully consistent with the hypothesis that the first step of Parkinson’s disease is oxidative-stress damage to mitochondria. This automatically leads to an energy deficit in dopaminergic neurons, a condition that progresdively enforces a decline in their dopamine production. This in turn leads to the well-known and debilitating motor symptoms of the the disease such as slowness, stiffness and tremor.

If you would like to know more about the scientific justification for this experiment, please read “Resetting the Redox Balance to fight Parkinson’s disease.

The Protocol

Experimtnts and observations made by the suthor Dr Albert Wright, enabled a protocol to be defined for the preparation and dosing of Brassica seed extracts and a checklist for following up the evolution of symptoms over a period of weeks or months. This protocol, although was made available to a group of Parkinson’s disease sufferers in October 2020. A small number of them decided to commit to a program of self-experimentation, making their own broccoli tea and pooling their data for analysis.

Making sulforaphane from Brassica seeds

To get a good yield of sulforaphane from broccoli seeds or sprouts, the basic chemistry of the phytochemicals and enzymes in broccoli seeds must be taken into account. The seeds or sprouts contain three separate substances, glucoraphanin (a glucosinolate precursor of sulforaphane), myrosinase (an enzyme which catalyses the conversion of glucoraphanin to sulforaphane) and a co-enzyme ESP (epithiospecifier protein), which modifies the conversion of glucoraphanin to make an inactive byproduct. A high yield of sulforaphane can only be obtained when ESP is inactivated and the conditions are optimised to enable myrosinase to work efficiently. The conditions present in the gastrointestinal tract (temperature, pH), lead to low bioavailability of sulforaphane. At high temperatures the myrosinase enzyme is destroyed which totally blocks any production of sulforaphane. For these reasons, cooked broccoli contains very little sulforaphane. White mustard or daikon radish seeds contain versions of myrosinase which is more efficient than that in broccoli seed and can be used as replacement catalysts. Optimised hydrolysis conditions produce a cloudy yellow suspension which can be which filtered through a fine-mesh tea strainer to remove inactive particulate matter. This suspension contains highly bioavailable sulforaphane which will calm down Keap1 and let Nrf2 do its work.

Results

The results of this pioneering experiment are quite remarkable. They clearly show that a specific group of symptoms, collectively called non-motor symptoms respond strongly to this treatment over a period of just a few weeks, whereas motor symptoms remain practically unchanged over this short timescale.

Non-motor symptoms were strongly attenuated by broccoli seed tea whereas motor symptoms were unaffected.

These results are both encouraging and instructive. Encouraging, because they provide the first evidence that activating Nrf2 has an immediate and powerful impact on a subset of Parkinson’s disease symptoms. Instructive, because the distinction between non-motor and motor symptoms provides guidance about the mechanisms in action when Nrf2 impacts the health of neurons. This result was achieved by Parkinson’s patients taking coordinated action to improve their knowledge of the disease. They did it entirely on their own, in just 3 months and with no external funding. These Patients took action to become researchers and have succeeded where others dared not try. These results make two important statements:

  • A broccoli tea, rich in sulforaphane rapidly attenuates a subset of Parkinson’s disease symptoms,
  • There was a clear distinction in the response of non-motor compared to motor symptoms. This implies that at least 2 different mechanisms are involved in the genesis and/or resolution of Parkinson’s disease symptoms.

What more can we learn from the results of this patient-driven study?

The three symptoms which responded most strongly and progressively to the treatment were “fatigue, sleep quality and lack of motivation”. These symptoms have a strong association with energy production. This implies that the first direct impact of upregulating Nrf2 is to improve energy production in neurons, most likely by reducing ROS damage to mitochondria. If so, this could also break the vicious circle whereby mitochondrial damage, once established is self-sustaining because ROS damage to mitochondria creates more ROS which sustains more mitochondrial damage etc. In extreme cases it can get out of control. We can infer from this that oxidative stress is likely to be the dominant mechanism in the genesis of the process that leads to these non-motor symptoms. If confirmed, this mechanistic pathway should be the primary target to be investigated in any therapeutic plan to fight Parkinson’s disease.

Urinary incontinence and night time urinary frequency were also considerably improved. These are symptoms that strongly impact the quality of life of PwP.

Another important conclusion is that the natural isothiocyanates found in Brassica seeds have more than enough potency to reduce oxidative stress and rapidly attenuate non-motor Parkinson’s disease symptoms.

Resetting the Redox Balance to fight Parkinson’s Disease

After more than 12 month’s research and experimentation, a small group of Parkinson’s disease patients successfully carried out a 6-week study using a specially prepared Broccoli seed tea to reduce oxidative stress in neurons. This post gives the scientific context to the study and explains WHY they decided to try out this potentially disease-modifying therapy which has not been officially approved.


“Pilot study of broccoli seed tea by Parkinson’s Patients”
This article is now available in PDF format on the Documents page

If you prefer to learn about HOW this study was carried out and the results obtained, go to the “The broccoli seed tea experiment”. You can find this post here.

Albert F Wright, PhD

Introduction: Compelling evidence by leading researchers supports the hypothesis that a contributing factor in the aetiology of Parkinson’s disease is age-related divergence from normal redox balance in brain cells. This divergence allows excessive oxidative stress and inflammation to damage cells and disrupt neuronal function. The equilibrium between oxidants and antioxidants is controlled by the transcription factor Nrf2, the master regulator of antioxidant responses. The the activity of Nrf2 declines with age, leading to greater levels of oxidative stress.

The isothiocyanate sulforaphane, which can be made from broccoli seeds is able to activate Nrf2, and modify the redox balance.

After being diagnosed with Parkinson’s disease in 2018, I decided to explore this idea by monitoring my own symptoms in response to treatment by a specially-prepared broccoli seed extract. After 12 months of experimentation, I shared my observations and methods with a small number of Parkinson’s patients who were interested in testing the method for themselves. This is their story.

This hypothesis had never been tested for Parkinson’s disease in official clinical trials, but now a small group of Parkinson’s disease patients have demonstrated by their own efforts that a broccoli seed tea containing sulforaphane can improve their symptoms of Parkinson’s disease. This new study clearly shows that non-motor symptoms are strongly attenuated by this treatment whereas motor symptoms remain unchanged over the timescale of this experiment.

The Redox Balance System

Over the last 20 years highly-specialised research has demonstrated how cells use a gene-based system to maintain the balance between oxidants and antioxidants within a healthy range inside cells. We now believe that the set-point of this redox control system can drift out of the healthy range as we get older, opening the door to many chronic illnesses such as neurodegenerative diseases, cancer, heart disease etc. This Redox Balance System (RBS) can affect all cells, but is most active in brain, heart, urinary tract, gastrointestinal tract and endocrine tissues. It’s first job is to detect and rapidly destroy any excess oxidizing molecules and free radicals (Reactive Oxygen Species (ROS) and Reactive nitrogen Species (RNS)) as well as toxins that can damage cell membranes, mitochondria and DNA. ROS and RNS are automatically generated when cells make energy from glucose and oxygen. Brain cells, especially dopamine-producing brain cells, use more energy and create more ROS than other cells. The second job of the RBS is to fight excessive inflammation. Too much ROS and inflammation is bad for cells, but so is too little, since ROS and inflammation are the first linea of defence against infection and cancer. The RBS has built-in control processes to adjust ROS and inflammation up or down to meet changing conditions. There is however clear evidence, that in brain cells of people with Parkinson’s disease this system fails to keep ROS and inflammation within the healthy range at all times.

For a full scientific explanation of the mechanisms involved and how Brassica seed extracts can be used to combat the causes of Parkinson’s disease, click on the following link: Role of the transcription factor Nrf2 and Redox Balance in Parkinson’s Disease

For the scientific community, the RBS is called the Nrf2/Keap1/ARE pathway, after the 3 key players in this process. Don’t worry about the names, they are acronyms for the 3 proteins which have a specific function in maintaining the redox balance:

  • ARE (Antioxidant Response Elements) are enhancer sequences in promoter regions of the DNA of every chromosome. When activated, they initiate the mechanism to promote the transcription of groups of genes that express antioxidants, antioxidant enzymes and anti-inflammatory cytokines to combat oxidative stress and inflammation.
  • Nrf2 (Nuclear factor (erythroid-derived 2)-like 2) are signalling molecules (transcription factors) that locate to ARE and switch it on by binding to it.
  • Keap1 (Kelch-like ECH-associated protein 1) is the gatekeeper protein that regulates the flow of Nrf2 to ARE. It does this in response to signals from 27 sensors incorporated in the protein that detect the presence of ROS, RNS, toxins and electrophiles in every cell.

Under stable conditions, Nrf2 protein binds to docking sites of the protein dimer Keap1 in the cytoplasm and is degraded. When Keap1 is oxidised by ROS, electrophiles or sulforaphane, newly synthesised Nrf2 then migrates to the nucleus where it binds to ARE and promotes the transcription of antioxidant and anti-inflammatory genes. Illustration adapted from P. Hiebert and S Werner.

Whenever Nrf2 binds to ARE, the gene promoter function of ARE initiates the transcription of a battery of genes to produce antioxidant and detoxifying enzymes, anti-inflammatory cytokines and simultaneously suppresses inflammatory cytokines. Cytokines are small messenger proteins that generate or suppress inflammation. The function of these genes is to restore a healthy environment inside each and every cell to enable them to function correctly. The rate of production of these antioxidant and anti-inflammatory elements depends on the quantity of Nrf2 present in the nucleus close to ARE promoters. In dopamine brain cells of people with Parkinson’s disease, ARE promoters do not receive enough Nrf2 to restore this healthy environment. One way to resolve this is to subdue the activity of the gatekeeper Keap1, so that more Nrf2 protein can reach ARE and increase the expression of antioxidant molecules and enzymes. There are several natural molecules found in foods that are known to reduce the activity of Keap1, but they are not present in normal food in sufficient quantities to resolve this problem.

Calming down the Keap1 gatekeeper

It takes 2 molecules of Keap1 to form a dimer which can capture one molecule of Nrf2. Keap1 molecules are judges and administrators of the redox environment. They judge the levels of ROS in the cell using 27 different sensors that detect the presence of oxidants and toxins. The higher the levels of ROS detected, the more Nrf2 molecules get a free passage to relocate to the nucleus where they can switch on ARE and boost the production of antioxidant enzymes and anti-inflammatory cytokines. If the levels of ROS are judged to be low or satisfactory, the Nrf2 molecules are detained and destroyed by keap1. The process is designed to keep the level of enzymes and cytokines at the optimum level to maintain a healthy environment. For people with Parkinson’s disease, the RBS fails to maintain the optimum redox balance and levels of ROS are allowed to drift too high. The RBS controler needs to be adjusted to bring the ROS balance back into the range that keeps neurons healthy.

A partial explanation for the excessive levels of ROS may simply be found n the process that drives natural ageing. As we get older, our cells produce less Nrf2 and more Keap1. This altered ratio means that the flow of Nrf2 molecules to ARE is reduced such that ARE gets switched on less frequently, moving the redox range to a higher state of oxidative stress. Fortunately, we now know how to calm down Keap1 so that more Nrf2 can reach ARE. We must however be careful not to be too heavy-handed. If we increase Nrf2 too far or too fast the system is designed to react against such excesses and will automatically activate a negative feedback loop creating the opposite effect, albeit with a delay.

One way to calm down Keap1 is to supply it with “soft oxidant” molecules called electrophiles. Oxidation is the process whereby an atom or molecule loses an electron by transferring it to another atom or molecule. Strong oxidants like ROS, aggressively and permanently steal electrons from other tissues, a process that damages them. Electrophiles, on the other hand, are more moderate and temporarily “borrow” electrons. Electrophiles are strongly attracted to some of the Keap1 sensors which have electrons to lend. When a Keap1 sensor lends an electron this triggers the process to inactivate its gatekeeping function. The most active electrophiles in foods are found in cruciferous vegetables such as cabbage, broccoli, Brussels sprouts, mustard, and turnips. Isothiocyanates are what give these vegetables the reputation of being healthy foods, but are also responsible for their strong taste which some people find unpleasant. There are more than 100 different isothiocyanates in these plants, but the one we are most interested in is called sulforaphane and is present in broccoli. It is found in high concentrations in the seeds or sprouts (early seedlings). The vegetable only contains small amounts.

Can resetting the redox balance help Parkinson’s disease?

Resetting the redox balance system has not been officially tested on humans with Parkinson’s disease. In 2010, a leading neurologist, Dr Antonio Cuadrado proposed a Phase II trial using sulforaphane to reduce oxidative stress for Parkinson’s disease, in a human trial supported by 16 European hospitals. The Michael J. Fox Foundation for Parkinson’s disease turned down his request for funding. The reason given was:

“If it would show a relevant efficacy, no company would be interested in covering the huge cost of a Phase III trial for a natural compound that could not be patented.”

Put another way – “Well, even if it would benefit Parkinson’s patients, we will not support it since there is no financial incentive for pharmaceutical companies to develop such a therapy.” Over the ten years since this statement and despite considerable progress by researchers, no pharmaceutical company has shown any interest in using sulforaphane to treat Parkinson’s disease.


What can Parkinson’s patients do to break this deadlock?

Waiting will not help Parkinson’s patients!

The passive approach is to wait for pharmaceutical companies to synthesise and test new molecules that will do the same job as these natural isothiocyanates. Unlike natural molecules, synthetic ones can be patented and their potential revenue from drug sales can therefore be protected. Work on synthetic electrophiles started before the end of the last century, well before the Nrf2/Keap1/ARE pathway was fully understood. There are now many different synthetic molecules being tested for different conditions, but none for Parkinson’s disease. However, even if these synthetic molecules were proven to be effective for the treatment of Parkinson’s disease, it will take at least 10 years before they become available to patients.

Getting involved improves your knowledge and gives you a voice

The active approach is for Parkinson’s patients to test for themselves whether natural isothiocyanates could have an effect on their own symptoms. My own experiments and observations enabled me to set up a protocol for the preparation and dosing of Brassica seed extracts and a checklist for following up the evolution of symptoms over a period of weeks or months. This protocol, although far from perfect, was made available to a group of Parkinson’s disease sufferers in October 2020. A small number decided to try it out for themselves by following a program of self-experimentation, making their own broccoli tea and pooling their data. The results from this pioneering experiment are quite remarkable. They clearly show that a specific group of symptoms, collectively called non-motor symptoms respond strongly to this treatment over a period of just a few weeks, whereas motor symptoms remain practically unchanged over this short timescale.

Non-motor symptoms were strongly attenuated by broccoli seed tea whereas motor symptoms were largely unaffected.

Interesting, but what does this mean?

Sceptics may say that this experiment wasn’t a proper double-blind trial with a placebo arm, so it’s probably just a placebo effect and doesn’t mean anything. So let’s check that out. There has been a lot of research on the placebo effect in PD. It turns out that when PD patients are given a placebo, but they think it might be the real drug, they get a positive effect. Because of the “expectation” that the drug may do some good, they think positive and their neurons make more dopamine. Great, and what does this extra dopamine do? Well, the extra dopamine makes movement easier and attenuates motor symptoms. That makes sense, but in this case motor symptoms were not improved, but the non-motor symptoms were improved. Well, so maybe there is some other explanation.

General fatigue was the most widespread non-motor symptom among the 8 PwP who took part in the experiment. All participants reported suffering from general fatigue and all 8 reported improvement or remission from fatigue at the end of the 6-week experiment. The total fatigue score was reduced by 90%. So let’s take a closer look at fatigue

Persistent fatigue, an overwhelming sensation of exhaustion unrelated to physical effort, is one of the earliest and most common symptoms reported by Parkinson’s disease patients, often occurring well before diagnosis and remaining throughout its progression. Fatigue has a major impact on quality of life of PD patients, but remains one of the least documented and least researched symptoms of PD. Fatigue is also a hallmark symptom of mitochondrial disease and markers of elevated oxidative stress and mitochondrial dysfunction correlate with disease severity of patients diagnosed with Chronic Fatigue Syndrome.

Taken together with previous knowledge, the results of this experiment are consistent with a more refined model in which mitochondria in dopaminergic neurons are the primary target of oxidative stress leading to compromised energy production in DA neurons.

Given the wealth of experimental data relating oxidative stress to mitochondrial dysfunction and compromised energy production in DA neurons, the omnipresence of fatigue reported by Parkinson’s disease patients is unsurprising. The remarkable attenuation of fatigue by the participants in the broccoli seed tea experiment is consistent with the hypothesis that sulforaphane, by upregulating the Nrf2/ARE pathway and neutralising oxidative stress is active in reducing mitochondrial dysfunction and restoring normal energy production in neurons. The relative rapidity of the effect also appears to be consistent with the dynamics of mitochondrial evolution and regeneration.

A theory for PD based on a cascade of 2 mechanisms

If the above hypothesis is correct, then it would appear that Parkinson’s disease progresses via 2 distinct steps.

Step 1: Oxidative stress creates mitochondrial dysfunction and reduced energy production

With increasing redox imbalance, oxidative stress damages mitochondria in highly-exposed neurons. This impairs the Complex 1 enzyme in mitochondria which is an essential enzyme in the process to make energy from glucose and oxygen. Reduction in Complex 1 automatically creates more ROS and sustains a vicious circle which amplifies the process. These neurons suffer an acquired but reversible version of chronic mitochondrial dysfunction through oxidative stress. The hallmark symptom of mitochondrial dysfunction is fatigue, a common non-motor symptom of Parkinson’s disease. Dopaminergic neurons are among the most highly exposed because of their high energy demands, but other neuron types are also very likely to be affected.

Step 2: Energy deficient DA neurons cannot sustain their normal dopamine production.

As their energy supply declines, an increasing number of DA neurons become less productive and may even shut down altogether. Some may eventually die. Dopamine availability will then decline to below the critical threshold for normal motor function, causing the appearance of motor symptoms. There is every reason believe that this cascade of events will continue as the disease advances.

A disease which progresses by 2 distinct mechanisms requires a therapeutic approach to address both steps. Current therapies only address the dopamine deficit which is responsible for motor symptoms of Parkinson’s disease. There is an urgent need to respond to mitochondrial dysfunction and the energy deficit acquired through oxidative stress to Complex 1 enzymes in all types of neurons.

Feedback: If you found this article useful or would like further information, please leave a comment below or contact me at the address given here.

Albert F Wright

Email: wriga38@patientresearcher.com