Why are diabetics more likely to develop Parkinson's disease?

Miquel Adrover, University of the Balearic Islands and Laura Mariño Pérez, University of the Balearic Islands

Surely, many of you will find it difficult to finish reading this article without the memory of a diabetic friend or family member coming to mind. Certainly, this exercise in empathy would have been much more unusual in the mid-1990s, when the prevalence of type II diabetes (DM2) in our country was only 3%. However, the combination of increasingly sedentary habits with an unhealthy diet has led to a current percentage of around 13.8%.

This increase is even more pronounced worldwide, especially in developed countries. In fact, 387 million people have already been diagnosed with DM2. The worst thing is that this number is expected to double by 2035, making DM2 a colossal pandemic.

The lock that doesn't work

DM2 appears as a result of the development of resistance to the action of insulin. This small protein acts as a glycolysis regulator hormone. Or what is the same, as a key that opens the cellular doors so that glucose can penetrate them and be transformed into energy.

Thus it is understood that if, for some reason, the insulin does not fit well in your lock, the glucose has no way to enter the cells and accumulates in the bloodstream (hyperglycemia).

In principle, this accumulation of glucose in the blood should not be a problem, since it constitutes the main source of energy for our body.

So why do diabetics have health problems? To understand it, we must delve into the chemical structure of glucose.

Its predominant molecular structure is shaped like a hexagon, with carbon atoms at five of its vertices and an oxygen atom at the sixth. This hexagonal shape is so stable that it normally prevents the formation of other, more reactive molecular structures. One of them is the linear form of glucose, minority (0.002% of the total) but very reactive against proteins and DNA. This, together with the carbonyl and dicarbonyl compounds formed during the autoxidation of the hexagonal form of glucose, makes hyperglycemia toxic.

But why? In essence, because these compounds are capable of reacting with our proteins, modifying the interactions that define their structures and, consequently, their biological functions. The process is known as protein glycation, and it is responsible for the development of retinopathy, nephropathy, or diabetic neuropathy.

Vulnerable brain

It has recently been found that protein glycation in brain neurons also stimulates the appearance of neurodegerative pathologies in diabetics. This correlation is relatively recent and the mechanisms behind it are not yet known. And of course, without this knowledge it is impossible to develop effective therapies that prevent its appearance.

Determined to close this gap, a few years ago we decided to undertake the molecular study of how glycation can cause Parkinson's. We started from an observational study, carried out in 2016 on almost 2 million patients, which showed that diabetics are 38% more likely to suffer from this neurodegenerative disease.

But first, let's make a point. Do we know why Parkinson's develops? To explain it we must travel within the neurons of the substantia nigra of the brain. In them we find a small protein that lacks a three-dimensional structure, alpha-synuclein (aS). This molecule is involved in the packaging (vesicular encapsulation) of dopamine, a key neurotransmitter in the brain. But also in its subsequent transmission between neurons. In other words, it is essential for neurons to be able to talk to each other.

If genetic factors (mutations) or sporadic (chemical modifications) appear that directly implicate aS, there may be consequences. Either their binding to vesicles is inhibited, or they end up being deposited within the cell and inducing neuronal death. Both processes involve a decrease in interneuronal communication and the appearance of the symptoms that characterize Parkinson's disease.

After this parenthesis, let us return to the analysis of the correlation between diabetes and Parkinson's. In addition to the observational results already discussed, it has been shown that aggregates of aS isolated from neurons of diabetic patients who died due to Parkinson's present a high density of glycation-derived compounds (AGEs).

The molecules that connect diabetes and Parkinson's

It was this fact that aroused a great number of concerns in us. Are these glycation end products formed on the protein in solution, or on the already precipitated protein (insoluble form) in the intraneuronal space? If they form on dissolved aS, can they cause it to agglomerate and precipitate? Perhaps they inhibit the interaction between aS and vesicles? Are they formed due to the increase in the products of intraneuronal glycolysis, or is it a posteriori, as a result of the carbonyl stress that occurred during neuronal death?

Diagram of the relationship between type 2 diabetes and Parkinson's. Author provided

Currently, all the efforts of our research group (Molecular Reactivity and Drug Design of the UIB) are focused on trying to answer these questions. For this we jointly use experimental techniques and computational methods.

So far we have managed to describe the effect of the modification of lysines, one of the most abundant amino acids in aS. We use Nε-carboxyethylisine (CEL), one of the AGEs detected in vivo that alters the conformation of the aS. We have also shown that it hinders the association of different aS molecules and their subsequent precipitation, as well as the binding of aS to vesicles, thus making their biological function impossible.

These results represent only the first stone that has to make it possible to link, from a molecular point of view, diabetes with Parkinson's disease. The generation of this knowledge will lead to the design of therapeutic strategies so that that family member or friend who currently suffers from diabetes has a lower risk of developing Parkinson's.

Miquel Adrover,, University of the Balearic Islands and Laura Mariño Pérez, Postdoctoral Researcher in Structural Biology, University of the Balearic Islands

This article was originally published on The Conversation. Read the original.