Cobbers on the Brain

Since April is Autism Awareness Month, it seems very fitting to learn about!

Autism is characterized by difficulty communicating, repetitive or obsessive behaviors, and sensitivity to light and materials. According to the CDC, 1 in 68 people in the US are diagnosed with an autism spectrum disease. Breaking that up even further, 1 in 42 boys and 1 in 189 girls. Children can be diagnosed as early as 2 years old, however it is usually not until age 4 or 6 in the case of Asperger’s disorder.

So why the gap between the genders? Signs of Autism Spectrum Disorder are often displayed more in men and boys such as the repetitive behaviors and lack of communication skills. However, girls tend to internalize behaviors are more likely to exhibit shyness that may be overlooked. Often times their fixation is something that other girls are likely to enjoy as well such as horses or animals. Females also tend to be more social beings and have more verbal skills then males which could contribute to the oversight. There is a hypothesis that a genetic contributor to the cause of autism is on the X chromosome (pictured in pink). Because males only have one, they are more likely to exhibit autistic tendencies than a girl with two X chromosomes.

Y and X chromosome

But beyond that, what is the cause? There are many misconceptions about its cause because it is very poorly understood. There are likely many contributing factors such as the environment, especially during development. If a mother gets sick or gets an infection during the pregnancy (especially during a critical time) it can increase the child’s risk for autism. Immunity problems in the mother, such as an autoimmune disease or fighting an infection, can produce antibodies in her body that can cross the placenta and interfere with fetal brain development. Often times if there is a disruption or abnormal function of the immune system in the fetus it can lead to inflammation causing even further damage.

An IgG that is able to cross the placenta.

It has also been seen that zinc deficiency during gestation plays a role in abnormal cell function as well. Zinc is very important in cell division, protein interaction, and healing. Low zinc levels have been found in people with autism. It is important to get the proper amount of zinc (12-13 mg/day) while pregnant or breast feeding.

Age of parents is also a risk factor, especially if the mother is older than 35 and the father is older than 40. It is important to also include genetic contributions as a potential contributing factors. There are mutated genes associated with autism, but no definitive relationship. Interestingly, some of the genes in question are related to zinc function in the body.

It is important that people are properly educated as to what is known about autism. When reading information about autism and its cause it is essential to check the credibility of the source and the studies that support it. People with autism can be very highly functioning, or may need a lot of help – that is why there is a spectrum. It is important to be respectful, understanding, and patient if people with autism have trouble communicating. We are making progress when it comes to awareness. Meet Julia, a little girl with autism who is the newest addition to the cast of Sesame Street!

It is very possible that your choices will prevent your child from developing autism, but those regarding vaccines will not. Recent research suggests a plethora of environmental prenatal factors that play an important role in a child developing autism. These include viral infection, zinc deficiency, abnormal melatonin synthesis, maternal diabetes, prenatal and perinatal stress, toxins, and parental age. But note that if these are prenatal, then administration of a vaccine once a child is born will not affect whether autism develops.
Let us observe these factors more deeply.

First, viral infection (of a pregnant mother). How could an infection cause autism in an unborn child? The answer lies in antibodies. Antibodies are a part of the body’s natural defense mechanism, meant to identify and eradicate foreign objects. And so it makes sense that, during a viral infection, a mother’s immune system increases its number of antibodies. This is great for the mother to stay alive, and these antibodies do not affect her in any negative fashion, but the fetus responds quite differently. Because antibodies can cross the placenta, they find their way into the bloodstream of the fetus, and through the developing “blood-brain barrier”. Here they disrupt normal brain development, and just so, may cause autism. Beware even further, that autoimmune diseases and intense allergies may cause a similar result.
Zinc deficiency has also been shown to increase risk of autism in developing fetuses. Take your vitamins, pregnant mothers. Because zinc is an important element in cell metabolism (namely gene regulation), a lack of the metal will force cells to develop poorly. Even further, high levels of copper can displace zinc and cause similar effects.

Melatonin synthesis is, of course, slight more out of one’s control. But the fact remains, abnormality in its synthesis is correlated with increased rates of autism. The results of this may be seen in the unique sleep-wake cycles of people with autism, as melatonin plays an important role in regulation of circadian rhythms.

Maternal diabetes is quite certainly out of the control of all parties, but it has been shown to be correlated with autism in children. The pathology is unknown however, and more research is necessary to know more about this factor.
Prenatal and perinatal stress may seem difficult to avoid, as having a bowling-ball-and-a-half hanging on your abdomen will certainly cause discomfort. But the increased levels of glucocorticoids and cytokines will not be beneficial to your child. These hormones can cause the immune system to turn into overdrive, and just as with the viral infections, we have seen why that is bad news.
Toxins are certainly bad for adults as well as children. Mercury, lead, thalidomide, valproic acid, and many other chemicals are shown to affect the human brain in adverse ways. With that said, adults are able to handle small doses associated with everyday life. But fetuses? Not so much. Of course, this was part of the scare with vaccines, as they contained minute amounts of mercury. Thankfully, however, this mercury has since been removed, and even if it were not, the mercury had been chemically bound in a non-toxic form.
Parental age can be a very important factor as well. As men age, their gametes (sperm) develop more and more mutations which are then passed on to children. Mutations of any sort are more-than-likely bad for an organism, and can certainly cause brain development issues. Increase age of mothers also has a correlation with autism, though likely through autoimmune disorders and pregnancy complications rather than mutations.

All of this shows that how we behave as “pre-parents” matters to the developing fetus. However, this also shows that children are born with autism, and are not going to develop the disorder from an injection after birth. Vaccinate your children; you will save lives.

Hmm…that title was a bit far-fetched. It was supposed to play off the adage “Don’t judge a book by its cover”. Regardless, I will get to my point: new research Parkinson’s disease has revealed a fascinating connection between seemingly unrelated proteins.
Parkinson’s disease is a long-term disease characterized by motor neuron degeneration, but in late stages also causes dementia (the picture below is from an 1886 book on neurological diseases). The motor symptoms result from the death of cells in the substantia nigra, a portion of the brain involved in movement and motor planning. The result of this is lowered levels of dopamine within the substantia nigra.

While the exact cause of the degeneration is unknown, years of research has been placed on the Lewy-bodies (congregations of proteins) that form within cells. Patients with Parkinson’s have an elevated level of these Lewy-bodies in their neurons, so it is natural to assume they play an important role.
A very prevalent protein involved in the formation of Lewy-bodies is α-syneuclein, the long, stringy protein pictured below. This protein’s main role in human cells is only vaguely understood (though it seems to be important in managing the bird songs of zebra finches). It is possible that the protein is an inhibitor of phospholipase D2, which means that more of this protein would result in lower levels of phosphatidic acid and choline, which are neurotransmitter precursors.

The way α-syneuclein accumulates into Lewy-bodies is through a process called aggregation. If the protein gets phosphorylated (usually this means “marked for degradation”) when it is not supposed to, it can clump with others to form these aggregates. Even further, the “prion effect” is seen with this phosphorylated protein, meaning that if it runs into healthy proteins, it can change them into unhealthy proteins, compounding aggregation.
So how do these healthy α-syneuclein’s get phosphorylated into their unhealthy versions in the first place? The answer may lie in GRKs.
Acronyms are great, aren’t they? GRK stands for G-protein coupled receptor kinase, which is a collection of words that essentially means “cell receptor deactivator”. These enzymes cycle through a cell and find cell receptors that are being activated too often. Since the cell no longer wants these activated, the enzyme phosphorylates it, which marks the receptor for death.
Here we again see the word “phosphorylates”. It was just this process that began the aggregation of α-syneuclein into Lewy-bodies. Recent studies have shown that these GRKs are able to phosphorylate α-syneuclein even though their structures insist that they should not. Prior to this research, there was no reason to believe that a GRK would play a role in Parkinson’s disease, as the enzyme regulates pathways quite unrelated to aggregation of proteins.

But here we see it, an enzyme phosphorylating a protein that its structure insists it should not. This is precisely where the title of this post fits in. It is so easy for researchers to think that they know everything and skip over some ideas because they believe them to be invalid.
In the end, however, research needs to be thorough for its own sake. The world works in very mysterious ways sometimes, and we need to check even the most remote possibilities if we are indeed set on learning more about this universe. Perhaps Parkinson’s disease may be cured because a few people decided to observe the effect of a random enzyme on α-syneuclein, even though the science told them they shouldn’t.

A common problem underlying many neurodegenerative diseases such as ALS, Alzheimer’s disease, and Parkinson’s disease is an abnormal accumulation of proteins in neurons.

In Parkinson’s the protein alpha-synuclein (pictured below) builds up in large masses called Lewy bodies. These bodies are toxic to the cell and can lead to cell death seen in Parkinson’s disease.

Parkinson’s Disease was first described by Dr. James Parkinson in 1817. The gene PARK encodes for the protein parkin (appropriately named after Dr. Parkinson). Parkin is a component of a clean-up system of the cell called the Ubiquitin Proteasome System or UPS (basically a fancy name for the garbage man of the cell). When a protein has an error or isn’t functioning properly, it is marked for death and the UPS system comes around to destroy it.  But because parkin is involved in this mechanism, it is not working properly in patients with Parkinson’s which allows the buildup of proteins leading to cell death.

(a proteasome chewing up a purple protein)

The current treatment for Parkinson’s disease is the drug L-DOPA which only deals with side effects of the disease and not the underlying protein build up. Parkinson’s specifically affects dopaminergic cells so they are not able to release sufficient amount of dopamine. Treatment with L-DOPA can help increase levels of dopamine in these patients and improve quality of life.

While there are many other molecular pathways thought to be involved in the progression of Parkinson’s this main concept of protein buildup is similar to that of other diseases. If we want to combat these neurodegenerative diseases, we can look into boosting our cells UPS system which naturally fights protein aggregation. In relation to Parkinson’s research, there are promising trials for drugs that will target and inhibit certain steps in the pathogenesis of Parkinson’s Disease specifically.

Michael J. Fox has started a foundation dedicated to finding the cure for Parkinson’s. He was diagnosed in 1991, and has been a large advocate for funding research since he released the statement of his diagnosis. They have raised $700 million for research programs for Parkinson’s. https://www.michaeljfox.org/