Lardy brains make Parkinson's disease mice worse
Article first published online: 20 AUG 2014
Published 2014. This article is a U.S. Government work and is in the public domain in the USA
Journal of Neurochemistry
How to Cite
Cookson, M. R. (2014), Lardy brains make Parkinson's disease mice worse. Journal of Neurochemistry. doi: 10.1111/jnc.12843
- Article first published online: 20 AUG 2014
- Manuscript Accepted: 25 JUL 2014
- Manuscript Received: 21 JUL 2014
The essential manipulation reported by Rotermund et al. (2014) is to change the diet of mice expressing the α-synuclein A30P mutation that causes Parkinson's disease (PD) in humans, from standard laboratory chow to a diet containing about ten times the amount of total fat. These mice have brainstem pathology that is reminiscent of PD and die a little earlier than wild type littermates. The essential results of Rotermund et al. (2014) are that the high-fat diet caused the A30P mice to die earlier and have greater numbers of phosphorylated α-synuclein pathology in the brainstem. Although all the details of the mechanism(s) are not completely worked out, the authors suggest that Akt phosphorylation might be involved (Rotermund et al. 2014).
To understand why the experiment might have worked, it might be helpful to consider the rationale for manipulating fats. One advanced by the authors is the idea that age is a major driver of PD risk and also a driver of metabolic disorders, specifically diabetes (reviewed in: Zhang and Tian 2014). The effects in humans are not huge. For example, in one study there was an ~ 80% increase in risk of PD if a person had diabetes prior to the development of their motor symptoms, although the number of cases with diabetes is small and therefore the confidence interval around the estimates are broad (Hu et al. 2007). Also, whether the human risk is related to diet, obesity, diabetes, aging or all (or none) of the above is hard to disentangle from the extant epidemiological data. Nonetheless, the available data suggests that manipulating diet in animals might be a reasonable way to manipulate pathology in animals.
Additionally, α-synuclein, the main pathological protein in PD, is a lipid-binding protein and there are some reasons to think that lipid binding is important in this proteins normal function (Antonny 2011) and pathogenesis (Cookson 2005). Specifically, the form of α-synuclein used here, A30P, has lower lipid-binding ability compared to the normal protein. Hence, manipulation of dietary lipids might affect PD-like pathology by mimicking a pro-pathological syndrome in the whole body and/or by changing brain lipid composition that might then change synuclein function. Determining which of these are critical is something that can be tested in future experiments. For example, increasing caloric content of food without changing lipid composition should impact the whole body with lesser effects on the lipid composition of membranes. However, at least one other recent study suggested that expression of a different mutant of α-synuclein (A53T, which does bind lipids) is associated with a resistant to diet-induced obesity. Therefore, the interactions between synuclein and diets are complex and need further resolution.
The other aspect of the study that is pragmatically important is the idea that our animal models can be improved, that is pathology can be promoted by factors other than gene manipulation. Many transgenic models only partially recapitulate human disease pathology within the lifespan of mice (Bezard et al. 2013). Therefore, having ways in which we can manipulate animals to promote neuronal damage might be particularly helpful. One limitation to simply making animals obese is that the manipulation itself might easily impact some motor phenotypes. However, if studying pathology is the main focus, then diet would be a reasonable and easy to perform adjustment to standard mouse housing conditions. It would be very interesting to see if a similar dietary manipulation provokes dopaminergic cell death in models such as viral over-expression of α-synuclein (Fiandaca and Federoff 2014). Such an approach might allow for the comparison of different mutant forms of α-synuclein.
One area where I am not certain how the results should be interpreted is whether this animal model supports a diabetes-PD link specifically, or a environment-gene link generally. On one hand, both this model and the reported epidemiological data point in the same direction (i.e., more diabetes/obesity with higher PD risk) even if both are relatively small effects. On the other hand, human epidemiology and mouse models are quite different and should each be considered separately in terms of their need to be replicated – and with small effect sizes the need for replication is very high. An additional argument against a common mechanism is that there have been genomewide association studies in both type 2 diabetes and PD that have nominated different genetic loci, suggesting independent mechanisms of risk of these two diseases. Identifying the detailed mechanisms of how diet induces α-synuclein pathology in the mouse model should be instructive for future directions in identifying disease mechanisms in human PD. For example, if there is a link between diet and kinase activation then one ought to be able to see the same activation in human samples, perhaps separating PD patients who had diabetes in lifetime from those that did not.
Overall, the study by Rotermund et al. (2014) provides some important new directions in understanding perhaps the mechanisms involved in human PD and provides an interesting way to make phenotypes in mice somewhat worse. How these types of approaches might be useful to understand other neurodegenerative diseases remains to be established.
Acknowledgments and conflict of interest disclosure
The author is an editor for Journal of Neurochemistry.
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