In Vitro Cell Culture Experiments
Immortalized fibroblasts
Mouse embryonic fibroblasts were cultured in DMEM supplemented with 10% fetal bovine serum and penicillin/streptomycin antibiotics. The immortalized WT and SIRT6 null fibroblasts were previously generated in the laboratory of and are a generous gift from Dr. Raul Mostoslvasky.
Primary neuronal cultures
Primary neurons were isolated from P0 mouse pups by a standard protocol modified for our study. Briefly, after dissection of neonatal brains, cortices were minced and digested in papain for 30;min at 30Co temperature. After that the solution was filtered through a 100;m filter and then fractionated in a sucrose gradient. The gradient fractions containing neurons were collected and re-suspended in Neurobasal Media, and cells were counted and plated on poly-D-lysine coated plates. The neurons were cultured in Neurobasal Media with physiological concentrations of glucose at physiological concentrations of oxygen and supplemented with bFGF and B27. Cultures were treated and analyzed 7;days after plating. Histochemical analysis performed on every batch of cells confirmed that cells were comprised of 75% neurons and 25% astrocytes. Proportions were identified by flow cytometry with the markers- NeuN and GFAP respectively . The neuron population included tyrosine hydroxylase expressing cells confirmed by SDS-PAGE analysis. Proportion of neural cell types were not changed between WT, SIRT6 KO, and OX cultures.
Flow cytometry & apoptosis analysis
Nicotine
Could A Nasty Habit Have One Actual Benefit
byJudy George, Senior Staff Writer, MedPage Today May 7, 2020
Male British physicians who smoked tobacco in 1951 had a 30% lower risk of death from Parkinson’s disease, an analysis of data from the British Doctors Study showed.
Moreover, doctors who continued to smoke over the years had a 40% lower risk of Parkinson’s mortality, reported Robert Clarke, MD, of the University of Oxford in England, and co-authors.
As shown in their study online in Neurology, Parkinson’s mortality risk was inversely associated with the amount of tobacco smoked, and for those who quit smoking, the effect was attenuated with increasing time since quitting.
The findings emerged from 65 years of follow-up with nearly 30,000 male physicians in Great Britain and should not be interpreted to promote smoking, but rather to foster a closer look at why smoking continues to be linked to lower Parkinson’s risk, Clarke said.
“Current smoking is the leading cause of premature death and disability worldwide, and any such hazards would greatly exceed any beneficial effects of current smoking on risk of Parkinson’s disease,” Clarke wrote in an email to MedPage Today.
Researchers first proposed that smoking may reduce Parkinson’s risk 60 years ago, noted Yuan Cheng, MD, and Yan-Jiang Wang, MD, PhD, both of Daping Hospital of Third Military Medical University in Chongqing, China, in an accompanying editorial.
Disclosures
Clarke and co-authors reported no disclosures.
Primary Source
Neurology
Does Smoking Reduce The Risk Of Parkinsons Disease Onset
A study of over 900 patients with parkinsonism in Olmsted County has revealed that the incidence of both parkinsonism and Parkinsons disease may in fact have increased during the last 30 year period. While confirmation is needed from other populations, the trend may suggest a possible association with lifestyle or environmental changes. The findings were published recently in Jama Neurology. Lead author, Walter Rocca , wanted to test a theory that was presented in a previous study analyzing the link between smoking and PD. Those authors concluded that smoking could be associated with a…
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What Is Parkinsons Disease
Parkinsons disease is a progressive condition that increasingly disrupts function in the brain.
It is the second most common degenerative disease of the brain after Alzheimers disease. Doctors give around 50,000 new Parkinsons diagnoses each year in the U.S., although this estimate varies.
Parkinsons disease causes degeneration in the central nervous system, disrupting movement, thought processes, and coordination.
The loss of brain cells that produce dopamine, an important neurotransmitter, causes the effects of this disease.
Symptoms develop gradually and may begin with small tremors in one hand. Parkinsons symptoms might include:
- facial, hand, arm, and leg tremors
- balance difficulties
Standard Protocol Approvals Registrations And Patient Consents
No relevant research ethics committees existed in 1951, when the British Doctors Study was designed and baseline questionnaires were sent. Doctors who chose to answer the first questionnaire were informed by investigators of the implications and methods of the study. Participants could choose to withdraw at any stage during follow-up, and all data were kept confidential.
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Nicotine Is Typically Thought Of As Bad For You An Addictive Substance That Can Get You Hooked On Cigarettes But New Research Has Found That Nicotine Can Help Protect Brain Cells From Damage Could The Benefits Of Nicotine Be Harnessed In A New Drug To Help Parkinsons
You may have read headlines that left you puzzled with regard to smoking and Parkinsons research suggests that smoking reduces a persons risk of developing the condition.
Weve known about this protective link for a while. Most recently, at the end of 2018, Imperial College London published a study that recorded the smoking status of 220,494 people aged 3770, and then assessed whether they went onto develop Parkinsons. The researchers found that:
- former smokers were 20% less likely to develop Parkinsons, and this increased to 50% in current smokers
- smoking more often was also linked to a decreased risk of Parkinsons
- passive smoking also reduced risk.
When the protective effects of smoking were discovered, it was met with confusion. We all know that smoking has huge health consequences and cant be recommended. Smoking is one of the biggest causes of death and illness in the UK. We now know smoking increases the risk of over 50 serious health conditions, from cancer and heart disease to stroke and dementia.
So how can we explain the news that smoking actually may reduce the risk of developing Parkinsons? Researchers think the surprising results could be explained by the nicotine found in tobacco.
Smoking Cessation And Parkinson’s Disease
Daniel D. Truong, MD
A number of studies have shown that the percentage of people who smoke is lower among individuals with Parkinsons disease than those without. Furthermore, individuals who have ever been smokers have half the risk of developing PD compared to those who have never smoked. When results like these were initially published, they were interpreted as showing that smoking somehow protected people from developing PD.
Recently, scientists have come to a different conclusion from these results. The new theory is that fewer people who go on to develop PD become or remain smokers because, for them, nicotine has less of a rewarding effect. Nicotine has a number of effects on the brain. Like all drugs that produce rewarding effects, nicotine increases levels of dopamine in certain areas of the brain. Behaviorally, it produces stimulating effects. Individuals with PD have a lower number of nicotine receptors in the brain, up to 50 percent lower in some areas, than those without PD. Because of this, there are fewer sites for it to bind to in the brain, so nicotines effects will be lesser. This may make it easier for people with PD to quit smoking.
If the reduced effect of nicotine on the brain is an early effect of PDone that is evident long before the motor effects are diagnosed, like changes in smell, constipation, and REM sleep disordersreduced nicotine reward and/or an easier time quitting smoking might be an early marker for PD.
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V Possible Mechanism Of Action
In light of the ETS and food studies, some researchers studying the causality suggested that the duration of exposure might be the most important neuroprotective factor against PD. Honglei Chen, a senior researcher at the National Institute of Environmental Health Sciences and a co-author of many smoking-PD studies, wrote that it is possible that the biological effects of nicotine or other tobacco compounds may be saturated at low concentrations. He added that since PD likely takes time to develop, sustained exposure may be needed to lower the risk . Other researchers proposed that smoking might have a protective effect not through direct action of a specific compound, but rather because chronic low dose exposure to smoke toxins can increase tolerance to acute exposures of other toxic compounds like -synuclein and A, which cause PD neurode-generation .
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Data on smoking habits were collected at recruitment, including whether participants were never, former or current smokers, their age when they started smoking and when they quit, and number of cigarettes per day at different ages.
The results showed that, compared with people who had never smoked, former smokers had a 20% lower risk and current smokers a halved risk for developing Parkinsons during follow-up .
Smoking more cigarettes and for a longer period of time were also associated with a lower risk of developing the disease, as the risk in people smoking 12 or more cigarettes a day or for longer than 30 years was about 55% lower compared to those who had never smoked.
Smoking correlated with reduced disease risk in both mid-age and late-onset Parkinsons, as well as in tremor-dominant and akinetic-rigid Parkinsons. Also, the risk did not vary over the follow-up period, which argues against a delaying effect of smoking on Parkinsons onset, the team observed.
Exposure to passive smoking at home or work was also linked to lower risk, as passive smokers were 30% less likely to develop the disease than non-exposed individuals.
In conclusion, the present findings are consistent with a protective effect of smoking on the risk of , scientists stated.
However, no one would ever be advised to use smoking as a preventive treatment for Parkinsons based on this research, because of the disastrous effects we know smoking has on peoples general health, Gallo added.
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Study: Alcohol Tobacco Use May Reduce Parkinsons Risk
Drinking alcohol and smoking tobacco may reduce a persons risk of developing Parkinsons disease, according to a new study that found evidence of a cause-and-effect relationship. It is crucial to be aware that smoking and drinking pose serious health risks to individuals, the researchers wrote, noting there was no clear…
Learning From Nicotine New Treatments
The evidence that nicotine could help people with Parkinsons has led to the search for new nicotine-like compounds that can help but arent addictive.
Two researchers funded by Parkinsons UK are teaming up to help find a new treatment Dr Mohammed Shoaib an expert in nicotine and Dr Mahmoud Iravani an expert in Parkinsons.
Dr Mohammed Shoaib has already designed new nicotine-like compounds that based on the way nicotine travels to the brain and increases neurotransmitters in the specific areas of the brain affected in Parkinsons. He has worked with Dr Mahmoud Iravani to design these compounds specifically for people with Parkinsons.
Now they want to know if the drugs improve memory and movement symptoms something that no current treatment can do. They are testing this in rodent models of Parkinsons. If successful, it will be an important step towards a new treatment that could be trialled in people with Parkinsons.
Parkinsons is a progressive neurological condition that affects about 145,000 people in the UK and an estimated 714 million people worldwide. There is currently no cure, and we desperately need better treatments.
You can help us speed up the development of new and better treatments, and a cure for Parkinsons by donating to this project today. 100% of your gift will go to supporting this research project.
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Smoking Associated With Lower Parkinson’s Disease Risk
- Date:
- JAMA and Archives Journals
- Summary:
- A pooled analysis of data from previous studies suggests that cigarette smoking appears to be associated with a reduced risk for developing Parkinson’s disease, with long-term and current smokers at the lowest risk, according to a recent report.
A pooled analysis of data from previous studies suggests that cigarette smoking appears to be associated with a reduced risk for developing Parkinson’s disease, with long-term and current smokers at the lowest risk, according to a report in the July issue of Archives of Neurology.
Several studies have suggested that patients with Parkinson’s disease are less likely to be smokers, according to background information in the article. “Recent studies also suggested that Parkinson’s disease risk is particularly low in active smokers with a long history of intense smoking; some even suggested dose-related risk reductions with increasing pack-years of smoking,” the authors write. “This prompted speculation as to whether and how these observations might inform Parkinson’s disease treatment and prevention.” However, the number of participants in most Parkinson’s disease studies is too small to answer important questions about the role of smoking.
Beate Ritz, M.D., Ph.D., of the UCLA School of Public Health, Los Angeles, and colleagues pooled data from 11,809 individuals involved in 11 studies conducted between 1960 and 2004.
Reference: Arch Neurol. 2007;64:990-997.
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I Smoking Cigarettes Protects Against Parkinsons Disease
The earliest association of the decreased risk of PD in smokers was discovered in 1959, in a collaborative study by the United States Public Health Service and the Veterans Administration. The study investigated the various causes of death of approximately 200, 000 U.S. government life insurance policyholders, who reported their tobacco use status and frequency. Smokers showed a dramatically lower mortality from PD. For those who smoked 10-20 cigarettes daily, the ratio of observed to expected deaths was 0.11 . Since then many studies and meta-analyses have been conducted on the subject. A meta-analysis of four cohort studies and 44 case-control studies showed that compared to never smokers, the relative risk of PD was 0.80 for former smokers , 0.59 for ever smokers , and 0.39 for current smokers .
The analysis of longitudinal data from 305, 468 participants of the NIH-AARP Diet and Health cohort, of whom 1662 had a PD diagnosis, clearly showed a positive association between the number of years of smoking and the reduced risk of PD. Compared to never-smokers, the odds ratio was found to be 0.78 for past smokers and 0.56 for current smokers. Additionally, the longer duration of smoking corresponded to diminished OR of Parkinsons. Regardless of the number of cigarettes smoked per day, the OR for those who smoked, for 1-9, 10-19, 20-29, 30-39, and 40+ years were respectively : 0.92 , 0.75 , 0.72 , 0.65 , 0.54 .
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Case Ascertainment And Sample Size
A total of 881 PD cases was ascertained in the participating EPIC centres. The present analysis has been conducted on a total sample of 214533 subjects after removing 147 prevalent PD cases, 5359 subjects with missing information on smoking status at recruitment. Moreover, 221 subjects with PD-like conditions were also removed from the analysis. The sample resulted in a total of 2666206 person/years. Procedures for PD case ascertainment in the EPIC cohort have been described elsewhere. In brief, in each centre, potential cases were identified through record linkage and validated through clinical record review by a neurologist expert in movement disorder who collected additional clinical data, including age of onset and clinical subtype at onset .
Loss Of Sirt6 Protects Neurons From Stress
To examine the causative relationship between SIRT6 and neuronal survival, we engineered brain-specific transgenic mice that either lack functional SIRT6 , or overexpress SIRT6 by about four-fold specifically in the brain. Noteworthy, the magnitude of SIRT6 overexpression in the brains of BSOX mice is comparable to SIRT6 increase in humans with PD-associated SNPs . We isolated primary neurons from WT, BSKO, BSOX mice, and challenged them with a broad range of insults relevant to PD pathology. Following challenge, neurons were stained with the apoptotic markers Annexin-V and propidium iodide , and their survival was measured using flow cytometry. Overall, SIRT6 KO neurons are better able to survive mitochondrial, oxidative, nutrient, and proteotoxic stress . Conversely, neurons that overexpress SIRT6 tend to have higher rates of apoptosis following these insults.
Fig. 3
We repeated the experiments testing the impact of SIRT6 and nicotine on cellular stress resistance in independently derived WT and SIRT6 KO fibroblast cell lines. As before, we found that SIRT6 KO fibroblasts have superior stress tolerance , and that nicotine protects cells from apoptosis in part through SIRT6 , confirming our initial observations.
Fig. 4
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Strategies To Minimize Reverse Causality Bias
The impact of reverse causality bias in observational studies can be minimized by ensuring that information about exposures is collected before the onset of the disease; excluding participants with previous disease at enrollment; and excluding a relevant period of early follow-up to minimize distortion of results by cases of disease that were undetected at enrollment. Hence, the first 10 years of follow-up were excluded from all analyses to minimize the effects of reverse causality bias.,,
Does Smoking Really Protect Against Parkinsons Disease
Written By Michael Greger M.D. FACLM on November 29th, 2018
The Centers for Disease Control and Prevention recently celebrated;the 50-year anniversary of the landmark 1964 Surgeon Generals report on smoking, considered one of the great public health achievements of our time and the first of 30 other such reports from the Surgeon General on smoking. Internal tobacco industry memos, which you can see in my Is Something in Tobacco Protective Against Parkinsons Disease?;video, document their response. Major criticisms of the report include a avalier treatment of costs of smoking: The Surgeon General argued that smoking costs the United States billions, but the tobacco industry noted that smoking saves the country money by increasing the number of people dying soon after retirement, so we dont have to pay for Social Security, Medicare, and the like. In fact, the industry argued, if we were truly patriotic, maybe we should encourage smoking to help balance the budget!
Quite unexpectedlyore than 50 studies over the last half century consistently;demonstrated;reduced prevalence of Parkinsons disease among smokers compared with never-smokers. Now there are more than five dozen studies.
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