According to the World Health Organization, smoking is responsible for approximately 6 million deaths in the world every year or one fatality every six seconds. 71% of all lung cancers and 42% of all chronic obstructive pulmonary diseases are attributable to tobacco use. Oddly enough, not everything related to smoking is bad news: smokers seem to be protected against Parkinson’s disease. Studies have shown that people who smoke on a regular basis are about two-fold less likely to suffer from Parkinson’s disease. A similar relationship exists between Parkinson’s and coffee. Nicotine and caffeine, both alkaloid chemicals, are stimulants which act on the sympathetic nervous system. The mechanism of protection against Parkinson’s disease is unknown in both cases; unveiling it would help both to increase the understanding of the disease and to develop strategies to treat it. Recent work published in the Journal of Neuroscience by Henry Lester and his team at Caltech sheds some light on the relationship between nicotine and Parkinson’s.
Parkinson’s disease is a neurodegenerative disease characterized by a resting tremor (an unintentional, rhythmic movement when the muscle is relaxed, most often in the hands). It is also characterized by rigidity in the muscles, which can be associated with pain, bradykinesia (slowness of movement), and postural instability. The origin of these effects seems to lie in the selective loss of a population of neurons that produce a neurotransmitter called dopamine. Aside from being involved in the reward pathway, dopamine is also critically involved in a brain circuit known as the nigrostriatal pathway, which is involved in the production of movement. When dopaminergic neurons in this pathway die, as in Parkinson’s disease, patients are left with the debilitating motor control issues mentioned above.
Although the causes of neuronal cell death are not well understood, aggregates (or clusters) of misfolded proteins are commonly found inside diseased cells. In a healthy cell, as much as one third of the proteins synthesized by the cell fail to fold correctly and require the intervention of a set of proteins called chaperones, which attempt to refold them. If they fail, the misfolded proteins are eventually eliminated from the system. In diseased cells observed in like Parkinson’s, misfolded proteins accumulate and aggregate, disrupting the normal function of the cell, eventually leading to its death.
So how might nicotine be protecting cells from dying in people with Parkinson’s disease? To answer this question, Dr. Lester and his team studied the effect of nicotine on dopaminergic neurons over time. To simulate the conditions that drive protein aggregation in dopaminergic neurons from Parkinson’s patients, the authors used a drug called tunycamycin, which affects normal protein folding. This response not only increases chaperone levels (which try to refold the misfolded proteins), but eventually activates proteins that promote cell death. The authors observed that in the presence of nicotine, the dopaminergic neurons were better able to counteract the toxic effects triggered by protein misfolding. Moreover, even blocking nicotine receptors did not alter this observation.
How is this possible? The authors hypothesize that nicotine permeates the plasma membrane and acts as a pharmacological chaperone inside the cell, reducing protein misfolding and protecting the cells against the formation of aggregates. Further work is needed to confirm this hypothesis, but the results open up the possibility of developing nicotine-based therapies that circumvent the obvious health problems associated with smoking.
There is, however, a better way to prevent Parkinson’s that will save you the trouble of cancer, lung disease, and bad breath: exercise! Exercise reduces your risk for Parkinson’s disease and many other pathologies, suggesting you might be better off spending your money on running shoes rather than in cigarettes. And even if you develop Parkinson’s disease, smoking tobacco is never medically justifiable. For this reason, researchers are working hard to isolate nicotine’s protective effects from the act of smoking per se to develop much needed treatments for patients with this debilitating disease.
Written by Ignacio Amigo.
Srinivasan R, Henley BM, Henderson BJ, Indersmitten T, Cohen BN, Kim CH, McKinney S, Deshpande P, Xiao C, and Lester HA. (2016) Smoking-Relevant Nicotine Concentration Attenuates the Unfolded Protein Response in Dopaminergic Neurons. Journal of Neuroscience 36(1):65-79. DOI: http://dx.doi.org/10.1523/JNEUROSCI.2126-15.2016