the phrase, “Mad as a Hatter” finds it’s origins in a story of serious human suffering.
In the early 19th century felt hat production soared. The cheaper hats where fashioned from rabbit fur which where roughened, to make them feel like the more expensive beaver fur, with a mixture of mercury compounds, the inhalation of which resulted in a condition the workers developed that has been dubbed mad hatters syndrome. Workers experienced symptoms of both a physical and mental nature. The physical ranging from trembling to a loss of teeth and the mental ranging from mood swings to fading memory.
Tubulin Molecule But how does a mercury compound cause such drastic symptoms? Essentially the main constituent of the mixture was mercury vapour (HgO) this releases mercury ions in to the brain which subsequently causes neural degeneration and it is this which I am going to explain. These mercury compounds inhibit the growth of neurones by stopping the polymerisation of a protein called tubulin and so to understand the way mercury ions affects the brain we need to understand the function and method of polymerisation of this protein. Tubulin is in fact made up of two subunits called the ?-subunit and ?-subunit these bind spontaneously after synthesis and once the two are bonded the unit is called a tubulin hetrodimer, and is shown in Figure 2.
You can see the two distinct separate subunits with the ?-subunit on the top. In figure 2 two pink molecules are clearly visible in the protein. This pink section is actually a molecule called Guanosine triphosphate (or GTP). The GTP molecule has the potential, like ATP, to be hydrolysed and give a diphosphate as well as releasing energy. However due to the structure of the protein only the GTP unit of the ?-subunit has the ability to be hydrolysed to GDP (Guanosine diphosphate) and release energy. Tubulin uses this release of energy to bind one tubulin hetrodimer to another, but as only the GTP can be used from the ?-subunit, when the proteins polymerise they line up with the ?-subunit of one tubulin binding to the ?-subunit of another creating a long chain called a protofilament (show in figure 3). These chains fold up and form cylindrical filaments often as a helix.A Protofilament
A MicrotubalThese are called microtubules, and play a pivotal role in every cell in nearly every living organism. They grow and shrink, by altering nature of the polymerisation of tubulin, carrying out essential functions in every cell. They are integral to cell division and play a role in moving thing around the inside of a cell often encapsulated in a bubble of membrane.
These microtubules (shown in figure 4) play a vital role in the way the brain works. In the brain microtubules provide the support for the 3D structure or cytoskeleton of a neurone, as well as tubulin, this cytoskeleton is made up by another protein called actin. In figure 5 you can see a growth cone of a neurone where actin has been stained red and tubulin has been stained green. The growth cones extend, by the polymerisation of tubulin, towards other neurones.
Their growth is coordinated by an extremely complex system of chemical direction in the surrounding matrix. These guide the growth cones to other neurones where they form synapses. And it is this interaction between brain cells and formation of synapses that allows the passage of electrical impulses and subsequently allows the brain to work by A growth conemoving these messages about. If a neurone was unable to extend a growth cone, and then as a consequence unable to find a synaptic partner, it would be rendered useless and this is afflictively how mercury ions disrupt a neurone. In figure 6 you can see how drastically the addition of mercury causes a growth cone to become dysfunctional. A growth cone before exposure and 120 then 240 seconds after exposure to extremely high Hg concentrations.
We can explain this returning back to the structure of tubulin. Mercury binds to the ?-subunit where GTP should be, displacing it and thus altering the structure of the protein. This means there is no GTP to release energy needed for hetrodimers to bond to one another so tubulin cannot polymerise, as the polymerisation is dependant on the release of this energy to allow the breaking and reforming of bonds.
As a consequence of this microtubules can’t grow. This means the cytoskeleton collapses and growth cones loose their structure, the growth cones can’t extend themselves as directed by chemical instructions. So synapses cannot form and consequentially electrical impulses aren’t passed between adjacent neurones. As parts of the brain become incapable of working to the necessary level, the symptoms of mad hatter’s syndrome become apparent.
Outside of felt hat production mercury compounds still poses health issues, the best example of this being tooth fillings. Despite not bringing out the elaborate characteristics Lewis Carroll portrays in Alice in wonderland, in high concentrations mercury can cause the extirpation of microtubules thus resulting in seriously problematic malfunctioning of parts of the brain.
Duh! 
