Herpes Simplex virus and Alpha-Synuclein

The theory of universal gravitation is not cast-iron. No theory is, and there is always room for improvement – Isaac Asimov

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Previously we have discussed the possibility that a virus could be one of the causative agents in Parkinson’s disease (Click here for that post).

Well, recently an interesting research report was published that offers evidence to support that idea and proposes an interesting new idea:

Title: Humoral cross reactivity between α-synuclein and herpes simplex-1 epitope in Parkinson’s disease, a triggering role in the disease?
Authors: Caggiu E, Paulus K, Arru G, Piredda R, Sechi GP, Sechi LA.
Journal: J Neuroimmunol. 2016 Feb 15;291:110-4.
PMID: 26857504

In this study, the researchers began with a simple hypothesis:

Pathogens that resemble normal proteins in the body may cause the immune system to attack cells that have those normal proteins.

A pathogen is a biological entity that can cause damage or disease in our bodies. Our immune system’s response is to generate antibodies – small proteins that label the pathogen as foreign (or ‘not self’). The removal cells in the immune system then know which stuff in the body to attack and which to leave alone.

But what happens if parts of a particular pathogen look very similar to a normal protein in the body? Causing an immune response through a process of ‘molecular mimicry’. This is the question that the scientists behind today’s study were asking.

To test their hypothesis, the scientists looked at the herpes simplex virus 1 and compared it with the Parkinson’s disease-related protein, alpha synuclein. They found that there were two regions on the herpes simplex virus 1 that exhibited the same appearance as regions on the alpha synuclein protein.

Importantly, when they analysed the blood of people with Parkinson’s disease and some age-matched control, they found a statistically significant difference in the levels of antibodies generated against of those one regions of the Herpes simplex virus 1 (that regions was Ul4222–36) in people with Parkinson’s disease. Those antibodies were also reactive to a site on the alpha synuclein protein (that region was 100–114).

The researchers suggested that the results may implicate the involvement of Herpes simplex virus 1 in stimulating immune cells against the alpha synuclein resulting in neurons that have a lot of alpha synuclein in the brain being attacked (especially those that have alpha synuclein containing Lewy bodies).

What is Herpes simplex virus 1?

Herpes simplex virus. Source: Wikipedia

Herpes simplex virus 1 and 2 are members of the herpesvirus (Herpesviridae) family of viruses that infect humans. The two viruses should not be confused – Herpes simplex virus 1 produces cold sores, while herpes simplex virus 2 is associated with genital herpes.

Both herpes simplex virus 1 & 2 are not only able to infect neurons in the brain, but they can able to become dormant and hide in neurons, away from the immune system. They can remain in that state until suddenly/spontaneously becoming reactivated for reasons unknown.

Is there any association between Parkinson’s disease and Herpes simplex virus 1?

There is one paper published in 1993, that found an association between previous exposure to Herpes and developing Parkinson’s disease:

Title: Infections as a risk factor for Parkinson’s disease: a case-control study.
Authors: Vlajinac H, Dzoljic E, Maksimovic J, Marinkovic J, Sipetic S, Kostic V.
Journal: Int J Neurosci. 2013 May;123(5):329-32. doi: 10.3109/00207454.2012.760560. Epub 2013 Feb 4.
PMID: 23270425

In this study, the researchers found that Parkinson’s Disease was also significantly associated to mumps, scarlet fever, influenza, and whooping cough as well as herpes simplex 1 infections. They found no association between Parkinson’s disease and Tuberculosis, measles or chickenpox though.

This result raises the tantalizing possibility that other viruses may be stimulating the immune system by ‘molecular mimicry’. Obviously this still needs to be tested. Plus that study was based only 110 people with Parkinson’s (compared with 220 controls) in one particular geographical location (Belgrade, Serbia).

Other than making the immune system attack cells, could the antibodies to the virus be having other effects?

In the discussion of their paper, the authors of the Herpes simplex virus 1 study point out that alpha synuclein can be divided in three parts:

1. the N-terminal region (which contains several of the point mutations related to early onset Parkinson’s disease)
2. the central region (which appears to promote aggregation)
3. the C-terminal portion (which tends to decrease protein aggregation)

The segment of alpha synuclein (100–114) that cross reacts with antibodies for Herpes simplex virus 1 (Ul4222–36) is part of the C-terminal region. Given that antibodies are binding to and removing to that non-aggregating section of alpha synuclein, are the remaining segments of α-synuclein left in place to foster aggregation (and perhaps forming Lewy bodies)?

Interesting research report that leaves us with new questions to explore.