The connection between coffee consumption and lower risk of Parkinson's disease has been known for a while. When I was applying for research assistant positions in 2006, one lab that interviewed me was studying the effects of caffeine in a mouse model of Parkinson's. Scientists began investigating this link after epidemiological studies based on large numbers of human patients showed that people who regularly consume coffee (and, to a lesser extent, other caffeinated beverages) are not diagnosed with Parkinson's disease as often as those who turn their noses up at the beverage of the gods (Elbaz et al., 2007). One interpretation of this trend is that something in coffee either ameliorates the symptoms of Parkinson's, or protects against the underlying cause of the disease -- death of the dopamine neurons in the substantia nigra of the brain. (The other possible interpretation is that some unknown factor, aka a "lurking variable," makes people both more likely to drink coffee and less likely to get Parkinson's.) Indeed, animal studies have already shown that giving mice caffeine and similar drugs protects against degeneration and death of their dopamine neurons in one model of Parkinson's disease (Kalda et al., 2006; Quik et al., 2008). Similar epidemiological studies indicate that tobacco users also have reduced risk of Parkinson's.
The authors of this paper wanted to test the effects of coffee and tobacco in another model organism, the fruit fly. For their study, they used two kinds of genetically-manipulated flies: one that overproduces the human alpha synuclein protein in dopamine neurons, and one with a mutation in the parkin gene. Alpha synuclein is the primary component of Lewy bodies, the abnormal protein aggregates seen in the neurons of Parkinson's patients. Mutations in the alpha synuclein gene (which is called SNCA) are known to cause some rare forms of familial Parkinson's disease. Similarly, mutations in parkin are linked to an inherited early-onset form of Parkinson's disease. Both types of flies exhibit degeneration and death of their dopamine neurons, making them a good model of the pathology of human Parkinson's disease. Additionally, parkin mutant flies exhibit abnormal climbing behavior and a reduced lifespan, similar to the movement disorders and other symptoms seen in human Parkinsonian patients.
Trinh et al. used lifespan, climbing behavior, and number of dopamine neurons in the brain as a measure of disease severity in mutant flies. The researchers wanted to test whether any of these characteristics were affected by exposure to coffee or tobacco.
In one of the more whimsical Materials and Methods sections I've read, they explain:
Coffee extracts were prepared using Starbucks House blend (Starbucks Corporation) or Tully House blend (Tully Corporation) for regular coffee and Starbucks decaffeinated House blend for decaffeinated coffee (Starbucks Corporation). Tobacco extracts were made using Eve light (Liggett) or Skoal Smokeless tobacco (Skoal) for regular tobacco and Quest2 (Vector Tobacco) for nicotine-free tobacco. Extracts were prepared by adding 18.4 g of ground coffee and 50 mg of dried tobacco separately to 100 ml of water and boiling for 30 min. The extracts were ... added to standard cornmeal–molasses fly food at varying concentrations.
After feeding coffee and tobacco extracts to the mutant flies, Trinh and colleagues dissected their brains to count their dopamine neurons. These were compared to the brains of mutant flies that did not receive the extracts. They observed that both parkin and SNCA mutant flies given coffee or tobacco extracts had more dopamine neurons than those given regular fly food. These results were significantly different, although upon perusing the graphs I noted that untreated flies had about 8-9 dopamine neurons in the relevant brain region, while flies given tobacco or coffee had 9-10. We're talking about a difference of one cell, here. (Although, if you put it another way, it's a difference of 10-12%!)
The authors then repeated this experiment on other flies, but replaced the coffee or nicotine extracts in the fly food with pure caffeine or pure nicotine. This time, they could not detect a difference in the number of dopamine cells between untreated flies of either genotype and flies treated with caffeine or nicotine. Another experiment using extracts from decaffeinated coffee and nicotine-free tobacco did show a significant effect, however. This led Trinh et al. to deduce that the protective effect of coffee and tobacco on the flies' dopamine neurons was not due to the action of caffeine or nicotine.
The researchers tested the effects of coffee and tobacco on mutant flies with other methods, as well. They fed decaffeinated coffee and nicotine-free tobacco extracts to parkin mutant flies and measured their lifespan and climbing ability. The mutant flies given coffee and tobacco were better climbers than untreated mutant flies -- they were able to climb a distance of 10 cm within 30 seconds in about 50% of climbing trials, as compared to untreated flies, who only completed the climb about 40% of the time. The treated flies also lived longer: although most mutant flies (treated and untreated) died by the age of 40 days, a few coffee- and tobacco-treated flies survived to 50 and 55 days, while none of the untreated flies did.
Trinh et al. went on to verify that coffee and tobacco extracts (regular and caffeine-/nicotine-free) significantly reduced neuronal degeneration in a cell culture model. Neuron cultures from mutant flies that overproduce alpha synuclein do not have very many dopamine cells; the extracts significantly increased the number of dopamine cells seen in such cultures. In fact, based on the graphs, the alpha synuclein cultures treated with coffee or tobacco seemed to have more dopamine cells than neuron cultures from normal flies! The researchers didn't explicitly test the effects of coffee and tobacco on normal neurons, however, so I can't say whether this difference is significant.
Finally, the authors suggest a mechanism for how coffee and tobacco might protect against neuronal degeneration in Parkinson's disease. They suggest that compounds in coffee and tobacco (including a molecule called cafestol) act on a transcription factor called Nrf2. Nrf2 normally activates genes that lead to increased production of an antioxidant called glutathione. Trinh and colleagues treated mutant flies with cafestol and saw results reminiscent of coffee and tobacco extract treatment. They also showed that coffee and tobacco lose their neuroprotective effects in mutant flies if they block the action of Nrf2, suggesting that the extracts are indeed acting in an Nrf2-dependent manner.
This paper leaves us with several questions. Perhaps the most relevant one is, why does decaffeinated coffee improve dopamine neuron numbers, climbing behavior, and survival in mutant flies, when other studies in mice implicate caffeine as the factor responsible for coffee's neuroprotective effects? There are several important differences between the fly and mouse disease models to consider. Aside from the obvious fact that mice are not flies (and thus, the two species differ in many aspects of their brain chemistry), the Parkinsonian mice used to study the effects of caffeine were generated by giving genetically normal mice a toxin that kills dopamine neurons. The fly model used in this study, however, is based on genetic mutations. Therefore, it's possible that caffeine is useful for protecting dopamine neurons from toxins, whereas other compounds in coffee and tobacco (like cafestol) can correct intrinsic problems that arise from mutations in a dopamine cell. The obvious next step is to test the effects of caffeine and decaffeinated coffee on genetic mouse models of Parksinon's disease, to see if the fly results can be repeated in mammals.
Of course, neither animal model of Parkinson's disease (toxins or mutations) is perfect. The vast majority of human Parkinson's cases are idiopathic, meaning that we don't know what caused the disease in these patients. Their symptoms cannot currently be explained by exposure to toxins or inherited mutations in genes like SNCA and parkin. Therefore, it's not clear whether caffeine or Nrf2-related factors like cafestol are responsible for the epidemiological trends seen between coffee or tobacco consumption and Parkinson's disease. At this point, scientists are still searching for what factor(s) might be shared between idiopathic cases of Parkinson's disease, in order to develop effective methods for preventing and treating the disease in these cases. In the mean time, though, studies like this one continue to expose new molecular pathways that might be relevant in neurodegenerative disease. And, of course, this particular paper helps justify my coffee habit, for which I am grateful.
Elbaz A., & Tranchant C. (2007) Epidemiologic studies of environmental exposures in Parkinson's disease. Journal of the Neurological Sciences 262: 37–44 DOI:10.1016/j.jns.2007.06.024
Kalda A., Yua L., Oztas E., & Chen J.F. (2006) Novel neuroprotection by caffeine and adenosine A2A receptor antagonists in animal models of Parkinson's disease. Journal of the Neurological Sciences 248(1-2): 9–15 DOI:10.1016/j.jns.2006.05.003
Quik M., O'Leary K., & Tanner C.M. (2008) Nicotine and Parkinson's disease: implications for therapy. Movement Disorders 23: 1641–1652 DOI:10.1002/mds.21900
Trinh, K., Andrews, L., Krause, J., Hanak, T., Lee, D., Gelb, M., & Pallanck, L. (2010). Decaffeinated Coffee and Nicotine-Free Tobacco Provide Neuroprotection in Drosophila Models of Parkinson's Disease through an NRF2-Dependent Mechanism Journal of Neuroscience, 30 (16), 5525-5532 DOI: 10.1523/JNEUROSCI.4777-09.2010