A few weeks ago I wrote a blog, "The Genius of Sheep". I learned that not only are sheep very smart, but they also may hold promise of a treatment for Huntington's Disease. Huntington's is a particularly cruel disease because its victims know what their fate will be. They will likely have watched a grandfather, mother, uncle or sister decline and die from the illness.

I was both interested to find out more about this sheep substance and was also skeptical of the claims for its curative powers. There's money to be made from raising the sheep and from extracting and marketing the substance.

However, I didn't understand the pathology of Huntington's, or neurodegenerative diseases in general. If I was going to write a blog--and that did become my ambition--a lot of work lay ahead. After doing that work, I learned one thing for certain: there is a profound gulf between what scientists know about neurodegenerative diseases and what they need to know in order to significantly help patients. Effective treatment, and even a cure, resides in bridging that gulf.

Woody Guthrie2 World Telegraph photo at Library of congress public.jpg

I think the first person who brought the tragedy of Huntington's Disease home for me was Woody Guthrie. Guthrie was a folk singer and political activist who battled Huntington's for the last years of his life. He died in 1967. Two of his children died of the disease, and his father did also.

GM1 Ganglioside

My quest for understanding the mechanics of Huntington's and other neurodegenerative diseases began with research into the mysterious sheep substance, GM1 ganglioside. This substance is found not only in sheep, but also on cell membranes of all animals. GM1 performs many functions throughout the body, but plays an especially important role in signalling: it helps nerve cells (neurons) to communicate with each other, to receive and transmit messages.

A Critical Balance

Nature, it turns out, is whimsical in its distribution of GM1 ganglioside. Some people have too much---- that's called gangliosidosis--and some people have too little.

Among the people who have too little are those afflicted with Parkinson'sand Huntington's. This is where sheep come into the picture, because some of them have gangliosidosis-- way too much GM1 ganglioside. This is a genetic affliction. By manipulating the genes of sheep--creating transgenic sheep--scientists are able to produce whole flocks that have gangliosidosis.

Trials were conducted in which mice suffering from Huntington's were given ovine--sheep-- GM1 ganglioside (directly into the brain). These mice showed significant improvement. There have also been trials that tested the effectiveness of GM1 ganglioside on symptoms of Parkinson's disease. This research used human subjects. Bovine--cow--ganglioside was used. The results of these trials showed that GM1 did ameliorate symptoms of Parkinson's.

Bovine GM1 is no longer used because of mad cow disease (the material is harvested from brains). If GM1 is to be used therapeutically, it will have to come from sheep.

Tay-Sachs Disease: A Hereditary Gangliosidosis in Humans

Tay-sachsUMich Jonathan Trobe, M.D. 3.0.jpg

Tay-Sachs is an autosomal recessive disease, which means a child has to inherit two copies of the gene to be affected. Hallmark cherry-red spots may be evident the eyes of those afflicted. Children usually do not survive past early childhood.

GM1 Ganglioside and Alzheimer's

It's important to note that what may be therapeutic for one neurodegenerative disease may have the reverse effect in another. An illustration of this: recent research indicates that GM1 ganglioside may actually accelerate the development of Alzheimer's disease. The destructive beta-amyloid protein (hallmark of Alzheimer's) binds to GM1 ganglioside in the brains of Drosophila--the fruit fly. The is significant for people because it turns out that the neural connectivity of a fruit fly is remarkably similar to a human's. So research on the fruit fly brain, it is believed, offers good insight into how human neuron messaging works. If beta-amyloid binds to GM1 in a fruit fly's brain, it may show the same inclination in humans.

Fruit Fly

Drosophila 2 melanogaster_-_side_André Karwath aka Aka 2.5.jpg

So GM1ganglioside may help alleviate symptoms of Parkinson's and may accelerate the progress of Alzheimer's. We know that it alleviates symptoms of Huntington's. How? I pulled up an article that described the neutralizing effect of GM1 on the disease causing-agent in Huntington's, a protein called mutant Huntingtin (mHTT). According to the article, in studies on transgenic mice (bred to have the disease) infusion of GM1 into the brain weakened the toxic effects of mHTT. Treated mice demonstrated normal motor function.

Transgenic Mice with Huntington's

These mice were bred with the mutant HTT gene. They are part of an experiment to see if environment can influence the progress of the disease. This video shows the mice interacting in what is described as their playground.

Where does all of this information leave researchers? It leaves them with a lot of unanswered questions. It's obvious that GM1 ganglioside has great potential as a subject of research. Will that research lead to understanding neurodegenerative disease? Will it lead to treatments, or cures? Some people think so. At the moment transgenic sheep (sheep bred with the gene to develop gangliosidosis) are being raised with the hope that they will be part of a treatment plan for Huntington's and Parkinson's diseases.

Neurodegenerative Diseases

Neuroconnectivity: it is the basis of the communication network that keeps our bodies functioning.

A Ballet in Which One Misstep Brings Disaster

Synapse Schematic Thomas Splettstoesser (www.scistyle.com) CC 4.0.jpg

As I look at this diagram, I am struck by how ordered it seems. The role of each part of the synapse is so clear. And then my eye catches one piece,"Voltage Gated Ca2+ Channel". This is such a small part, so easy to overlook. And yet, this one piece once held the key to my brother's future. A few years ago, a mysterious encephalitis suddenly overcame him. It defied diagnosis. He had seizures, dementia, movement disruption. Then a brilliant doctor put the bits of the diagnostic puzzle together and concluded that my brother had autoimmune voltage-gated encephalitis. A tiny piece of the synapse, shown in the illustration, was being attacked by my brother's own immune system. Massive doses of immune suppressive drugs, and plasmapheresis, stopped the attack.

The Synapse

The basic function of a neuron is to transmit information. The transmission of information between neurons occurs across a tiny space, a synapse. This transmission is dependent upon a host of factors, including neurotransmitters, which are like chemical railways. They carry information from one neuron to another.

In 2016 a group of neuroscientists got together to consider disturbances in synapses as a unifying characteristic of neurological disorders. The featured topic at the 2016 symposium was Synaptopathies: synaptic dysfunction in neurological disorders. A report came out of the conference. This suggested that a clue to causes, treatments and cures for many diseases of the brain might be found in studying synapse disturbance. The conferees were not only addressing neurodegenerative diseases, but also other conditions such as Downs Syndrome, autism and epilepsy.

Neurodegenerative

Three neurodegenerative diseases already mentioned in this post--Alzheimer's, Huntington's and Parkinson's--are often compared with one another (by neurologists). It is thought that in understanding the process that leads to illness in each of the three, an understanding of the underlying disease processes for all may emerge.

PET scan of parkinsons patient after fetal tissue NIH public.jpg

In Parkinson's Disease there's a disruption in dopamine delivery because dopamine receptors are destroyed. One therapeutic approach is to implant fetal tissue in the brain of a patient. In these before and after images, you can see that there is an increase in dopamine uptake a year after the surgery.

Amyloid Proteins

A recent study (2017) discovered a significant similarity between the way these three neurological diseases spread through the brain (and also chronic traumatic encephalopathy-- injury from sports concussions). In each case there seems to be a rupture within a cell that has encircled a pathogenic protein. The rupture results in dispersal of the disruptive protein. In the case of Parkinson's the protein is α-Synuclein, in Huntington's it's polyglutamine-expanded huntingtin, and in Alzheimer's it's β-amyloid and tau.

This is a montage of three images showing neurons affected by the mutant HTT protein. The yellow orb with tendrils is an affected neuron. The orange blob in the middle of that orb represents huntingtin proteins (HTT) collecting together abnormally in an inclusion.

One result of this blossoming protein field is plaque formation, or protein clumping. Although many of us have heard that plaques are a diagnostic feature of Alzheimer's, these plaques are also present in Huntington's and Parkinson's.

In Huntington's the aggregation of proteins in the brain is referred to as "clumping".

A factor the three disease have in common is cell death. In each of the three diseases a misfolding protein has been identified as instigating cell death. A 2013 article in "Frontiers in Molecular Biosciences" states, "...there is increasing evidence that in general, smaller soluble toxic misfolded oligomers are the main causative agent for neurodegeneration."¹

Glutamate: An Essential Neurotransmitter

Glutamate: Not Enough in Huntington's. Too Much in Parkinson's and Alzheimer's

Glutamate is a vital neurotransmitter. We need it in our synapses—80% of all messages sent from one neuron to another use this neurotransmitter.

Glutamate is excitatory, which means it promotes action. Even though it is an amino acid, we can't get it from our diets because of the blood brain barrier. So we have to manufacture it, in our brains. This happens in an exquisitely balanced process called the Glutamate-GABA-Glutamine Cycle. An important part of that cycle is the astrocyte, a cell that is abundantly dispersed throughout the brain.

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Huntington's: Not Enough

The astrocyte is like a transfer terminal. Once glutamate has been used in a synapse, it is sent over to an astocyte for processing. Processing means converting glutamate to glutamine, and then sending the glutamine off to a neuron, where it will be changed back into glutamate. This keeps the brain humming with enough glutamate to carry on its work effectively.

However, sometimes the glutamine never leaves the astrocyte. If that happens, then new glutamate won't be made, and there will be a deficit of this vital neurotransmitter. That's exactly what happens in Huntington's. With a deficit of glutamate, there is a disruption in the transmission of nerve impulses.

Parkinson's: Too Much

As has already been established here, glutamate is an excitatory neurotransmitter. There are also inhibitory neurotransmitters. These depress activity. An important inhibitory transmitter is GABA. Ideally, these two neurotransmitters--a positive and a negative, an excitatory and inhibitory--will be in balance. In Parkinson's that balance is disrupted in favor of glutamate. There's too much excitatory transmission. So much excitement, that neurons are damaged, and even killed.

This is where GM1 ganglioside seems to be helpful. It seems to have anti-excitatory properties and neutralize the effects of glutamate. This will spare nerve cells that would otherwise die.

Alzheimer's: A Devastating, Unregulated Release

In Alzheimer's, there is also a toxic bombardment of excitatory glutamate The result is the death of neurons and loss of function. Some medicines that have been formulated to ameliorate (temporarily) the symptoms of Alzheimer's symptoms try to stem the unregulated flow of glutamate.

Causes

Of the three diseases considered here--Alzheimer's, Huntington's and Parkinson's--only the cause of Huntington's can be explained with absolute clarity. It is a genetic disease. It is dominant, which means, if you inherit the disease from either parent, you will become ill. The disease is caused by a mutant gene, huntingtin (there are normal huntingtin genes, also.) The severity of the symptoms is influenced by the number of generations that have passed it along. The more generations, the more severe the disease is likely to be. Although becoming symptomatic is inescapable for those who inherit the gene, apparently environment can play a role in modifying the course of the disease.

Huntington's_disease_(5880985560) National Institute of Standards and Technology public.jpg

The red dots show a section of the gene called CAG (cytosine-adenine-guanine) sequence. The top gene is a normal huntingtin (HTT) gene. The bottom gene is the mutant huntingtin (mHTT). Note several repeats of CAG in the mutant gene. The more repeats of CAG in the gene, the more severe the disease will tend to be. With each generation that passes Huntington's along, repeats are added.

Alzheimer's also has a genetic component, although this is not a direct cause and effect relationship as it is in Huntington's. There is familial Alzheimer's. But, as with Huntington's, it seems that lifestyle can influence the age of onset and the course of the disease.

Formation of Plaques in Alzheimer's

Alzheimers2 beta amyloid plaque formation NIH public.jpg

In the diagram you can see a protein,Beta-amyloid 42, breaking off and joining together with others to make plaques--a hallmark feature of Alzheimer's Disease.

Of the three diseases, Parkinson's has the least clear genetic association, although there are families where it does seem to occur more frequently. There is also Familial Parkinson's, which is caused by a gene mutation. In most cases, environment and experience are believed to play a significant role in the development of Parkinson's disease.

I began writing this blog because I had questions. The questions began with GM1 ganglioside, but in order to understand that I need to learn more about neurodegeneration. This is not one disease, or three diseases. Each disease, it seems teaches us about the others. In reading different articles--and I was sure to reference those published in the last couple of years--so much information was speculative, or tentative. It's obvious that our understanding the brain, the part of our bodies that controls everything we do and know, is in its infancy.

I can't leave this post without acknowledging a debt to the animals that have suffered and died so that we may understand ourselves.

Sources

I did a lot of background reading for this piece. Most of the sources mentioned here were directly referenced.

One of my sources was @chappertron. He described (in one of his comments) the effect that varying levels of glutamate had on different animals. That sent me reading in a very productive direction. Thank you, @chappertron!

References

Footnote

¹ Frontiers in Molecular Biosciences Protein Misfolding and ER Stress in Huntington's Disease Talya Shacham, Neeraj Sharma, and Gerardo Z. Lederkremer