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Szelechowski M, Bétourné A, Monnet Y, Ferré CA, Thouard A, Foret C, Peyrin JM, Hunot S, Gonzalez-Dunia D. A viral peptide that targets mitochondria protects against neuronal degeneration in models of Parkinson's disease. Nat Commun. 2014 Oct 21;5:5181. PubMed.
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National Institute on Aging
The paper by Szelechowski et al. is very interesting and another example of how studying viruses can lead to insights into broader biological processes. I find it intriguing that viruses that are dormant in neurons might protect their cellular hosts by limiting damage that could normally lead to neurodegeneration. If this is a general phenomenon, we might be able to find other ways to protect neurons against the normal low levels of stress we expect them to be under throughout their lifespan. In this particular paper, the axonal protection was particularly impressive. Such protection might be helpful, as the authors state, for those disorders that we currently view as being related to mitochondrial function in axons, especially where the damage is thought to be cell autonomous.
The one area of caution for me is that the MPTP model has an uncertain relationship to PD pathogenesis. While it is clear that people with MPTP exposure get PD-like symptoms, and some forms of parkinsonism are related to loss of function in mitochondrial processes, it is less clear if MPTP is a good model for all aspects of PD. MPTP provides a great way to lesion the intact nervous system and is reported to damage axons, but it would be very interesting to see if protein-X is active in other models. For example, it is reported that axonal damage occurs in rats where α-synuclein is overexpressed (Lundblad et al., 2012). This might make an interesting second model in which to try this neuroprotective strategy. A protein that is also protective in α-synuclein models might be valuable to pursue further as a therapeutic strategy for PD and related disorders.
References:
Lundblad M, Decressac M, Mattsson B, Björklund A. Impaired neurotransmission caused by overexpression of α-synuclein in nigral dopamine neurons. Proc Natl Acad Sci U S A. 2012 Feb 28;109(9):3213-9. PubMed.
Universities of Manchester and Oxford
I agree with Brian Balin's comment on Madolyn Bowman Rogers' article about the intriguing effect of the Borna disease virus X protein, and would add only that it is in the interest of Borna and other viruses not to kill cells as in doing so, the virus too would succumb. In the case of HSV1, entering a state of latency in the host is a means of survival, providing a permanent reservoir of virus, despite frequent reactivations leading to productive infection and cell death.
On the theme of a viral role in AD, It is worth stressing that there are now some 80 papers by several groups (including those by Lovheim and colleagues), including 40 from mine, that directly or indirectly support the role of HSV1 in AD. These are striking in their use of remarkably diverse approaches—epidemiological, virological, genetic, and cell biological. My recent review (Itzhaki, 2014) summarizes them and explains certain relevant concepts in the hope that they will be better understood by those in the AD field who oppose a viral role. In fact, opposition to a role of HSV1 in AD has been expressed in a mere two publications, 11 and 13 years ago, in which the authors described their inability to detect HSV1 DNA in elderly and AD brains; however, six papers by groups other than mine have detected HSV1 DNA in such brains.
As for treating AD with antivirals with the aim of reducing disease progression, studies on three antivirals that act by different mechanisms have recently been published by my group (Wozniak et al., 2011; Wozniak and Itzhaki, 2013; Wozniak et al. 2013). Each antiviral was found to reduce substantially the accumulation of Aβ and phospho-tau that occurs in HSV1-infected cell cultures. The antiviral most likely to be used for therapy, acyclovir (or in practice its biodrug, valacyclovir), is very safe, and has the great advantage over many other treatments for AD that it targets only infected cells. Also, it should reduce or stop all viral damage, including the accumulation of Aβ and p-tau, irrespective of whether they are actual causes of the disease. There have been 413 AD trials between 2002 and 2012, with a failure rate of 99.6 percent (Cummings et al., 2014). Surely the time is now ripe for a clinical trial of an antiviral to combat HSV1 in the disease.
References:
Itzhaki RF. Herpes simplex virus type 1 and Alzheimer's disease: increasing evidence for a major role of the virus. Front Aging Neurosci. 2014;6:202. Epub 2014 Aug 11 PubMed.
Wozniak MA, Frost AL, Preston CM, Itzhaki RF. Antivirals reduce the formation of key Alzheimer's disease molecules in cell cultures acutely infected with herpes simplex virus type 1. PLoS One. 2011;6(10):e25152. PubMed.
Wozniak MA, Itzhaki RF. Intravenous immunoglobulin reduces beta amyloid and abnormal tau formation caused by herpes simplex virus type 1. J Neuroimmunol. 2013 Apr 15;257(1-2):7-12. PubMed.
Wozniak MA, Frost AL, Itzhaki RF. The helicase-primase inhibitor BAY 57-1293 reduces the Alzheimer's disease-related molecules induced by herpes simplex virus type 1. Antiviral Res. 2013 Sep;99(3):401-4. PubMed.
Cummings JL, Morstorf T, Zhong K. Alzheimer's disease drug-development pipeline: few candidates, frequent failures. Alzheimers Res Ther. 2014;6(4):37. Epub 2014 Jul 3 PubMed.
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