Medical Hypotheses 83 (2014) 637–639
Contents lists available at ScienceDirect
Medical Hypotheses journal homepage: www.elsevier.com/locate/mehy
Do genetic factors protect against Parkinson’s disease? What I can learn from my healthy grandma
a r t i c l e
i n f o
Article history: Received 3 August 2014 Accepted 30 September 2014
a b s t r a c t Parkinson’s disease (PD) is a progressive, neurodegenerative disorder and it affects 4–5% of people age 85 years or older. The etiopathogenesis of PD is a consequence of interaction between two factors, environmental pathogens and genetic susceptibility. If an environmental agent such as a toxin or pathogen were to play a major role in the causality of PD, it would need to be something relatively ubiquitous in our environment since we cannot find a specific population at risk. On the other hand, all efforts to implicate specific genetic sequences in risk of PD were futile since the great majority of PD cases are sporadic; however, if the majority of the population is exposed to a culpable environmental factor and only 5% of the population 85 years or older manifest the disorder, this raises an important question: Why and how does vast majority of the population not manifest with PD? It seems that we should investigate the certain genome or epigenetic alterations of the unaffected 95%. This large non affected population might have PD but they are not yet symptomatic and some may not be so for at least another 10 or 20 years. To further address this issue, we should screen and study the population that have been exposed to the environmental factor but with high certainty are not yet affected. Therefore the perfect population would be non-PD subjects who are 90 years or older. We believe the following are the unmet research needs that deserve more attention in PD. (1) More genetic studies. Comparison should be between PD subjects and non-PD control subjects who are 90 years old and above. (2) Study the mechanism of action of the candidate genes, as a subsequent examination of their gene products may lead to the discovery of neuroprotective agents in the disease. Ó 2014 Elsevier Ltd. All rights reserved.
Introduction Parkinson disease (PD) is not a very common disease, as it affects only 1–3% of the population over 65 years old and 4–5% of people age 85 years or older [1]. One of the most important risk factors for PD is aging. The etiology of sporadic PD is not well known, and genetic and environmental factors are implicated. There is extensive literature on genetic factors in sporadic PD but the majority of the cases have no distinct genotype. The genetic association with sporadic cases after 65 years old is very rare. In approximately 10% of the cases, genetic alterations have been established as a risk factor for PD and these alterations are usually seen in patients with onset before the age of 50 [2]. Studies of early-onset PD were initially identified six genes mainly by linkage analyses of Mendelian forms of PD. SNCA (synuclein alpha) and LRRK2 (leucine-rich repeat serine/threonine-protein kinase 2), were dominantly inherited genes [3], while PARK2 (parkin), PARK6 (PINK1 or PTEN-induced kinase protein 1), PARK7 (protein DJ-1) and PARK9 (ATP13A2) recessively inherited genes [4]. Candidate gene approach which is based on the knowledge of specific gene function and its pathway related to PD pathogenesis, although less http://dx.doi.org/10.1016/j.mehy.2014.09.024 0306-9877/Ó 2014 Elsevier Ltd. All rights reserved.
successful, suggested few genetic alterations mainly based on identifying loci detectable by linkage analysis. The genome-wide association studies (GWASs) further identified several risk loci for idiopathic PD such as SNCA, MAPT (microtubule-associated protein tau), BST1 (bone marrow stromal cell antigen 1), GAK (cyclin Gassociated kinase) and HLA-DR [5–9]. The follow-up GWAS studies, however, showed inconsistent findings for some loci. Conclusive data are still pending mainly because of the low power to surpass the threshold for genome-wide significance. The aggregate datasets by meta-analysis also provide inconsistent evidence for major risk genes [10]. On the other hand, previous efforts to link the environmental factors and PD have not been conclusive with only a few established risk factors. These risk factors include exposure to pesticides, herbicides, heavy metals and other chemicals. However, the majority of people exposed to the above environmental hazards are not affected with PD. Resultantly epidemiologists believe that further studies are needed to support environmental hypotheses [11]. The dogma in the field remains non-committal and experts commonly echo a blended thesis such as ‘‘the etiopathogenesis of PD is a consequence of interaction between two factors,
638
K. Dashtipour / Medical Hypotheses 83 (2014) 637–639
environmental pathogens and genetic susceptibility’’. This generalization does not seemingly enhance our perception or understanding and despite significant progress and advancement in basic science research, genetics, epidemiology and environmental science, we still do not have a strong, creative, cohesive and wellaccepted hypothesis regarding the etiopathogenesis of PD. Hypotheses Hypotheses: certain genetic factors protect us against neurodegenerative disorders including PD If an environmental agent such as a toxin or pathogen were to play a major role in the causality of PD, it would need to be something relatively ubiquitous in our environment since we cannot find a specific population at risk. Attempts to correlate risk of developing PD to a specific occupation, chemical or lifestyle have also not been consistently successful. Additionally, the clinical history of patients with PD does not suggest a random or specific exposure that is being shared among the majority of the affected cases. This suggests there may be an omnipresent environmental factor that all of us are exposed to with only a small percentage of people ultimately affected. The current thinking considers the multiple genetic susceptibility loci that make up a small part of the population susceptible to the environmental factors but as was mentioned above the genetic association with sporadic cases was not very successful. Another explanation could be based on the process of natural selection if we assume that the biological traits that brought about resistance to this environmental factor (whatever it may be) have become commonplace in our population. If only 4–5% of people greater than 85 years old develop PD after being exposed to the hypothetical environmental factor, it would be more useful to investigate a genotype that protects most people against this hazard rather than looking for a genetic factor that causes the disease. Recent evidence supports the hypothesis that many complex traits including neurodegenerative disorders may be influenced by a combined action of multiple protective and disease gene products that may be biologically important through their joint effects [12–14]. The interaction of genetic factors with each other or with environmental factors through epigenetic modification and thereby changing the gene expression can be potentially important in susceptibility to PD. Epigenetic modifications are the key interface between environment and genome, which are considered changes in gene activity and expression that are not caused by changes in DNA sequence [15]. Epigenetic modifications are an important source of genomic variation that would not be detected by GWAS. These changes accumulate over time in response to lifestyle and environmental exposures and subsequently affect gene regulation and explain the progressive nature of most common diseases [16]. Examples of mechanisms that induce such alterations are DNA methylation and histone modification. Altered DNA methylation in the brain has been observed in many neurodegenerative diseases [17]. Several studies have found aberrant methylation of several genes related to the pathogenesis of PD [18–20]. Now let’s be more specific about this omnipresent hypothetical factor in our environment. A growing body of evidence indicates that a-synuclein can spread between neurons and cause PD in a prion-like fashion [21]. The most convincing evidence for this comes from the post mortem evaluation of PD patients who had received grafts of fetal mesencephalic brain tissue [22]. Autopsies show that the surviving grafted neurons contain pathologic Lewy body-like protein inclusions 11–16 years later after procedure. Recently Masuda et al. established a new mouse model of sporadic synucleinopathy after inoculation of insoluble synuclein fibers from the brain of patients with Diffuse Lew Body Dementia [23].
If a-synuclein has a prion-like property and can spread in our body affecting previously healthy tissue, then why can’t it spread in our environment in a prion-like fashion? If this were that case, it seems that almost 95% of the population age 85 years or older are immune and remain unaffected. Even if we consider a prion particle as a pathogen for PD, we still do not classify PD as a contagious disease. In fact, the majority of couples or first-degree families of PD cases do not succumb to this disorder. A recent study looking for a a-synuclein in the colon biopsies of PD patients showed the 100% sensitivity to detect the disease but some controls showed positive for synucleinopathy as well [24]. Interestingly, the false positives belonged to subjects who had a first degree family or partner with PD. This provides more evidence in favor of a causative environmental factor. Therefore, if we consider a pathogen such as a prion, as the etiology of PD and if only 5% of people get affected, then we might consider the remaining 95% of the population as the healthy carriers or those who might be converted to symptomatic subjects sometime in the future. One can argue that it seems unlikely that PD results from ‘‘prion-like’’ spread in the environment, since the known transmissible human prion diseases (new variant CJD and Kuru) are exceedingly rare in the population and similar transmission could not account for the much more common PD. To better understand this, we need to re-evaluate the possibility of the genetic factor as the etiology of PD. All efforts to implicate specific genetic sequences in risk of PD were futile since the great majority of PD cases are sporadic; however, if the majority of the population is exposed to a culpable environmental factor and only 5% of the population 85 years or older manifest the disorder, this raises an important question: Why and how does vast majority of the population not manifest with PD? It seems that we should investigate the genome of the unaffected 95%. The complex difficulty with this large population is that they might have PD but they are not yet symptomatic and some may not be so for at least another 10 or 20 years. To further address this issue, we should screen and study the population that have been exposed to the environmental factor but with high certainty are not yet affected. Testing the hypothesis Who are the members of this population? The perfect population would be non-PD subjects who are 90 years or older. This population is an ideal study cohort as they have been exposed for the longest amount of time to this culpable, omnipresent environmental factor and still have not developed symptoms. It seems that instead of focusing on a small percentage of genetically affected PD patients, we should be studying this older unaffected population. Instead of searching for the genes that cause the disease, we should perhaps be trying to identify the genes that protect us. If we can identify specific genes that may protect us against PD, it is possible that their gene products might direct us to the discovery of a definitive neuroprotective agent. The New England Centenarian Study (NECS) and Elixir began in the last 10–20 years as a population based study of all centenarians living in New England [25]. The 90+ study cohort was initiated in 2003 in southern California to determine features associated with longevity including genetic and environmental factors [26]. As a result of these studies, the genetic signatures of longevity and the genotype that predicts longevity were proposed recently [27,28]. More genetic studies based on these and similar cohorts to identify and investigate genes that protect against neurodegenerative disorders including PD are warranted. To determine that any ‘‘protective’’ genetic variants in this population are specific for PD and not factors protective for cancer, heart disease or any other disease that would lead to earlier death, we should conduct more genetic studies but comparison should be
K. Dashtipour / Medical Hypotheses 83 (2014) 637–639
between PD groups and non-PD control subjects who are 90 years or older. The following are the unmet research needs that deserve more attention in PD. They are relevant to other neurodegenerative disorders as well.
[11]
[12] [13]
(1) More genome-wide association studies and DNA methylation pattern analyses (Genome-wide analysis of DNA methylation patterns). Comparison should be between PD subjects and non-PD control subjects who are 90 years old and above. (2) Study the mechanism of action of the candidate genes to find the possible neuroprotective proteins.
[14] [15] [16]
[17]
It seems that the genome of our witty grandparents may have the last say!
[18]
Conflicts of interest statement [19]
Dr. Khashayar Dashtiour has received honoraria or payments for consulting, advisory services, or speaking services from Allergan, Ipsen Biopharmaceuticals, Lundbeck, Teva Neuroscience, UCB, US World Meds, and Merz. There is no conflict of interest related to this article.
[20]
[21] [22]
References [23] [1] Kowal SL, Dall TM, Chakrabarti R, Storm MV, Jain A. The current and projected economic burden of Parkinson’s disease in the United States. Mov Disord 2013;28:311–8. [2] Martin I, Dawson VL, Dawson TM. Recent advances in the genetics of Parkinson’s disease. Annu Rev Genomics Hum Genet 2011;12:301–25. [3] Sundal C, Fujioka S, Uitti RJ, Wszolek ZK. Autosomal dominant Parkinson’s disease. Parkinsonism Relat Disord 2012;18(Suppl. 1):S7–S10. [4] Lopez G, Sidransky E. Autosomal recessive mutations in the development of Parkinson’s disease. Biomark Med 2010:713–21. [5] Simón-Sánchez J, Schulte C, Bras JM, Sharma M, Gibbs JR, Berg D, et al. Genome-wide association study reveals genetic risk underlying Parkinson’s disease. Nat Genet 2009;41:1308–12. [6] Maraganore DM, de Andrade M, Lesnick TG, Strain KJ, Farrer MJ, Rocca WA, et al. High-resolution whole-genome association study of Parkinson disease. Am J Hum Genet 2005;77:685–93. [7] Do CB, Tung JY, Dorfman E, Kiefer AK, Drabant EM, Francke U, et al. Web-based genome-wide association study identifies two novel loci and a substantial genetic component for Parkinson’s disease. PLoS Genet 2011;7:e1002141. [8] International Parkinson Disease Genomics Consortium, Nalls MA, Plagnol V, Hernandez DG, Sharma M, Sheerin UM, Saad M, et al. Imputation of sequence variants for identification of genetic risks for Parkinson’s disease: a metaanalysis of genome-wide association studies. Lancet 2011;377:641–9. [9] Saad M, Lesage S, Saint-Pierre A, Corvol JC, Zelenika D, Lambert JC, et al. Genome-wide association study confirms BST1 and suggests a locus on 12q24 as the risk loci for Parkinson’s disease in the European population. Hum Mol Genet 2011;20:615–27. [10] International Parkinson’s Disease Genomics Consortium (IPDGC); Wellcome Trust Case Control Consortium 2 (WTCCC2). A two-stage meta-analysis
[24]
[25] [26] [27]
[28]
639
identifies several new loci for Parkinson’s disease. PLoS Genet 2011;7:e1002142. Wirdefeldt K, Adami HO, Cole P, Trichopoulos D, Mandel J. Epidemiology and etiology of Parkinson’s disease: a review of the evidence. Eur J Epidemiol 2011;26(Suppl. 1):S1–S58. Cornetta T, Ptrono C, et al. Epidemiological, clinical and molecular study of a cohort of Italian. Cell Mol Neurobiol. Surguchov A. Synucleins: are they two-edged swords? J Neurosci Res 2013;91(2):161–6. Hill-Burns EM et al. A genetic basis for the variable effect of smoking/nocotine on Parkinson’s disease. Pharmacogenomics J 2013 Dec;13(6):530–7. Slatkin M. Epigenetic inheritance and the missing heritability problem. Genetics 2009;182:845–50. Ho SM, Johnson A, Tarapore P, Janakiram V, Zhang X, Leung YK. Environmental epigenetics and its implication on disease risk and health outcomes. ILAR J 2012;53:289–305. Urdinguio RG, Sanchez-Mut JV, Esteller M. Epigenetic mechanisms in neurological diseases: genes, syndromes, and therapies. Lancet Neurol 2009;8:1056–72. Desplats P, Spencer B, Coffee E, Patel P, Michael S, Patrick C, et al. Alphasynuclein sequesters Dnmt1 from the nucleus: a novel mechanism for epigenetic alterations in Lewy body diseases. J Biol Chem 2011;286:9031–7. Jowaed A, Schmitt I, Kaut O, Wüllner U. Methylation regulates alpha-synuclein expression and is decreased in Parkinson’s disease patients’ brains. J Neurosci 2010;30:6355–9. Matsumoto L, Takuma H, Tamaoka A, Kurisaki H, Date H, Tsuji S, et al. CpG demethylation enhances alpha-synuclein expression and affects the pathogenesis of Parkinson’s disease. PLoS One 2010;5:e15522. Olanow WC, Brundin P. Parkinson’s disease and alpha synuclein: is Parkinson’s disease a prion-like disorder? Mov Disord 2013;28:31–40. Kordower JH, Chu Y, Hauser RA, Freeman TB, Olanow CW. Parkinson’s disease pathology in long-term embryonic nigral transplants in Parkinson’s disease. Nat Med 2008;14:504–6. Masuda-Suzukake M, Nonaka T, Hosokawa M, Oikawa T, Arai T, Akiyama H, et al. Prion-like spreading of pathological alfa-synuclein in brain. Brain 2013;136:1128–38. Shannon KM, Keshavarzian A, Mutlu E, Dodiya HB, Daian D, Jaglin JA, et al. Alpha-synuclein in colonic submucosa in early untreated Parkinson’s disease. Mov Disord 2012;27:709–15. Sebastiani P, Perls TT. The genetics of extreme longevity: lessons from the new England centenarian study. Front Genet 2012;3:277. Kawas CH. The oldest old and the 90+ study. Alzheimers Dement 2008;4(1 Suppl. 1):S56–9. Grady DL, Thanos PK, Corrada MM, Barnett Jr JC, Ciobanu V, Shustarovich D, et al. DRD4 genotype predicts longevity in mouse and human. J Neurosci 2013;33:286–91. Sebastiani P, Solovieff N, DeWan AT, Walsh KM, Puca A, Hartley SW, et al. Genetic signatures of exceptional longevity in humans. PLoS One 2012;7:e29848.
⇑
Khashayar Dashtipour Loma Linda University School of Medicine, Department of Neurology, 11370 Anderson, Suite B-100, Loma Linda, CA 92354, USA ⇑ Address: Department of Neurology/Movement Disorders, Loma Linda University School of Medicine, 11370 Anderson, Suite B-100, Loma Linda, CA 92354, USA. Tel.: +1 909 558 2120; fax: +1 909 558 5837. E-mail address: [email protected]
Contents lists available at ScienceDirect
Medical Hypotheses journal homepage: www.elsevier.com/locate/mehy
Do genetic factors protect against Parkinson’s disease? What I can learn from my healthy grandma
a r t i c l e
i n f o
Article history: Received 3 August 2014 Accepted 30 September 2014
a b s t r a c t Parkinson’s disease (PD) is a progressive, neurodegenerative disorder and it affects 4–5% of people age 85 years or older. The etiopathogenesis of PD is a consequence of interaction between two factors, environmental pathogens and genetic susceptibility. If an environmental agent such as a toxin or pathogen were to play a major role in the causality of PD, it would need to be something relatively ubiquitous in our environment since we cannot find a specific population at risk. On the other hand, all efforts to implicate specific genetic sequences in risk of PD were futile since the great majority of PD cases are sporadic; however, if the majority of the population is exposed to a culpable environmental factor and only 5% of the population 85 years or older manifest the disorder, this raises an important question: Why and how does vast majority of the population not manifest with PD? It seems that we should investigate the certain genome or epigenetic alterations of the unaffected 95%. This large non affected population might have PD but they are not yet symptomatic and some may not be so for at least another 10 or 20 years. To further address this issue, we should screen and study the population that have been exposed to the environmental factor but with high certainty are not yet affected. Therefore the perfect population would be non-PD subjects who are 90 years or older. We believe the following are the unmet research needs that deserve more attention in PD. (1) More genetic studies. Comparison should be between PD subjects and non-PD control subjects who are 90 years old and above. (2) Study the mechanism of action of the candidate genes, as a subsequent examination of their gene products may lead to the discovery of neuroprotective agents in the disease. Ó 2014 Elsevier Ltd. All rights reserved.
Introduction Parkinson disease (PD) is not a very common disease, as it affects only 1–3% of the population over 65 years old and 4–5% of people age 85 years or older [1]. One of the most important risk factors for PD is aging. The etiology of sporadic PD is not well known, and genetic and environmental factors are implicated. There is extensive literature on genetic factors in sporadic PD but the majority of the cases have no distinct genotype. The genetic association with sporadic cases after 65 years old is very rare. In approximately 10% of the cases, genetic alterations have been established as a risk factor for PD and these alterations are usually seen in patients with onset before the age of 50 [2]. Studies of early-onset PD were initially identified six genes mainly by linkage analyses of Mendelian forms of PD. SNCA (synuclein alpha) and LRRK2 (leucine-rich repeat serine/threonine-protein kinase 2), were dominantly inherited genes [3], while PARK2 (parkin), PARK6 (PINK1 or PTEN-induced kinase protein 1), PARK7 (protein DJ-1) and PARK9 (ATP13A2) recessively inherited genes [4]. Candidate gene approach which is based on the knowledge of specific gene function and its pathway related to PD pathogenesis, although less http://dx.doi.org/10.1016/j.mehy.2014.09.024 0306-9877/Ó 2014 Elsevier Ltd. All rights reserved.
successful, suggested few genetic alterations mainly based on identifying loci detectable by linkage analysis. The genome-wide association studies (GWASs) further identified several risk loci for idiopathic PD such as SNCA, MAPT (microtubule-associated protein tau), BST1 (bone marrow stromal cell antigen 1), GAK (cyclin Gassociated kinase) and HLA-DR [5–9]. The follow-up GWAS studies, however, showed inconsistent findings for some loci. Conclusive data are still pending mainly because of the low power to surpass the threshold for genome-wide significance. The aggregate datasets by meta-analysis also provide inconsistent evidence for major risk genes [10]. On the other hand, previous efforts to link the environmental factors and PD have not been conclusive with only a few established risk factors. These risk factors include exposure to pesticides, herbicides, heavy metals and other chemicals. However, the majority of people exposed to the above environmental hazards are not affected with PD. Resultantly epidemiologists believe that further studies are needed to support environmental hypotheses [11]. The dogma in the field remains non-committal and experts commonly echo a blended thesis such as ‘‘the etiopathogenesis of PD is a consequence of interaction between two factors,
638
K. Dashtipour / Medical Hypotheses 83 (2014) 637–639
environmental pathogens and genetic susceptibility’’. This generalization does not seemingly enhance our perception or understanding and despite significant progress and advancement in basic science research, genetics, epidemiology and environmental science, we still do not have a strong, creative, cohesive and wellaccepted hypothesis regarding the etiopathogenesis of PD. Hypotheses Hypotheses: certain genetic factors protect us against neurodegenerative disorders including PD If an environmental agent such as a toxin or pathogen were to play a major role in the causality of PD, it would need to be something relatively ubiquitous in our environment since we cannot find a specific population at risk. Attempts to correlate risk of developing PD to a specific occupation, chemical or lifestyle have also not been consistently successful. Additionally, the clinical history of patients with PD does not suggest a random or specific exposure that is being shared among the majority of the affected cases. This suggests there may be an omnipresent environmental factor that all of us are exposed to with only a small percentage of people ultimately affected. The current thinking considers the multiple genetic susceptibility loci that make up a small part of the population susceptible to the environmental factors but as was mentioned above the genetic association with sporadic cases was not very successful. Another explanation could be based on the process of natural selection if we assume that the biological traits that brought about resistance to this environmental factor (whatever it may be) have become commonplace in our population. If only 4–5% of people greater than 85 years old develop PD after being exposed to the hypothetical environmental factor, it would be more useful to investigate a genotype that protects most people against this hazard rather than looking for a genetic factor that causes the disease. Recent evidence supports the hypothesis that many complex traits including neurodegenerative disorders may be influenced by a combined action of multiple protective and disease gene products that may be biologically important through their joint effects [12–14]. The interaction of genetic factors with each other or with environmental factors through epigenetic modification and thereby changing the gene expression can be potentially important in susceptibility to PD. Epigenetic modifications are the key interface between environment and genome, which are considered changes in gene activity and expression that are not caused by changes in DNA sequence [15]. Epigenetic modifications are an important source of genomic variation that would not be detected by GWAS. These changes accumulate over time in response to lifestyle and environmental exposures and subsequently affect gene regulation and explain the progressive nature of most common diseases [16]. Examples of mechanisms that induce such alterations are DNA methylation and histone modification. Altered DNA methylation in the brain has been observed in many neurodegenerative diseases [17]. Several studies have found aberrant methylation of several genes related to the pathogenesis of PD [18–20]. Now let’s be more specific about this omnipresent hypothetical factor in our environment. A growing body of evidence indicates that a-synuclein can spread between neurons and cause PD in a prion-like fashion [21]. The most convincing evidence for this comes from the post mortem evaluation of PD patients who had received grafts of fetal mesencephalic brain tissue [22]. Autopsies show that the surviving grafted neurons contain pathologic Lewy body-like protein inclusions 11–16 years later after procedure. Recently Masuda et al. established a new mouse model of sporadic synucleinopathy after inoculation of insoluble synuclein fibers from the brain of patients with Diffuse Lew Body Dementia [23].
If a-synuclein has a prion-like property and can spread in our body affecting previously healthy tissue, then why can’t it spread in our environment in a prion-like fashion? If this were that case, it seems that almost 95% of the population age 85 years or older are immune and remain unaffected. Even if we consider a prion particle as a pathogen for PD, we still do not classify PD as a contagious disease. In fact, the majority of couples or first-degree families of PD cases do not succumb to this disorder. A recent study looking for a a-synuclein in the colon biopsies of PD patients showed the 100% sensitivity to detect the disease but some controls showed positive for synucleinopathy as well [24]. Interestingly, the false positives belonged to subjects who had a first degree family or partner with PD. This provides more evidence in favor of a causative environmental factor. Therefore, if we consider a pathogen such as a prion, as the etiology of PD and if only 5% of people get affected, then we might consider the remaining 95% of the population as the healthy carriers or those who might be converted to symptomatic subjects sometime in the future. One can argue that it seems unlikely that PD results from ‘‘prion-like’’ spread in the environment, since the known transmissible human prion diseases (new variant CJD and Kuru) are exceedingly rare in the population and similar transmission could not account for the much more common PD. To better understand this, we need to re-evaluate the possibility of the genetic factor as the etiology of PD. All efforts to implicate specific genetic sequences in risk of PD were futile since the great majority of PD cases are sporadic; however, if the majority of the population is exposed to a culpable environmental factor and only 5% of the population 85 years or older manifest the disorder, this raises an important question: Why and how does vast majority of the population not manifest with PD? It seems that we should investigate the genome of the unaffected 95%. The complex difficulty with this large population is that they might have PD but they are not yet symptomatic and some may not be so for at least another 10 or 20 years. To further address this issue, we should screen and study the population that have been exposed to the environmental factor but with high certainty are not yet affected. Testing the hypothesis Who are the members of this population? The perfect population would be non-PD subjects who are 90 years or older. This population is an ideal study cohort as they have been exposed for the longest amount of time to this culpable, omnipresent environmental factor and still have not developed symptoms. It seems that instead of focusing on a small percentage of genetically affected PD patients, we should be studying this older unaffected population. Instead of searching for the genes that cause the disease, we should perhaps be trying to identify the genes that protect us. If we can identify specific genes that may protect us against PD, it is possible that their gene products might direct us to the discovery of a definitive neuroprotective agent. The New England Centenarian Study (NECS) and Elixir began in the last 10–20 years as a population based study of all centenarians living in New England [25]. The 90+ study cohort was initiated in 2003 in southern California to determine features associated with longevity including genetic and environmental factors [26]. As a result of these studies, the genetic signatures of longevity and the genotype that predicts longevity were proposed recently [27,28]. More genetic studies based on these and similar cohorts to identify and investigate genes that protect against neurodegenerative disorders including PD are warranted. To determine that any ‘‘protective’’ genetic variants in this population are specific for PD and not factors protective for cancer, heart disease or any other disease that would lead to earlier death, we should conduct more genetic studies but comparison should be
K. Dashtipour / Medical Hypotheses 83 (2014) 637–639
between PD groups and non-PD control subjects who are 90 years or older. The following are the unmet research needs that deserve more attention in PD. They are relevant to other neurodegenerative disorders as well.
[11]
[12] [13]
(1) More genome-wide association studies and DNA methylation pattern analyses (Genome-wide analysis of DNA methylation patterns). Comparison should be between PD subjects and non-PD control subjects who are 90 years old and above. (2) Study the mechanism of action of the candidate genes to find the possible neuroprotective proteins.
[14] [15] [16]
[17]
It seems that the genome of our witty grandparents may have the last say!
[18]
Conflicts of interest statement [19]
Dr. Khashayar Dashtiour has received honoraria or payments for consulting, advisory services, or speaking services from Allergan, Ipsen Biopharmaceuticals, Lundbeck, Teva Neuroscience, UCB, US World Meds, and Merz. There is no conflict of interest related to this article.
[20]
[21] [22]
References [23] [1] Kowal SL, Dall TM, Chakrabarti R, Storm MV, Jain A. The current and projected economic burden of Parkinson’s disease in the United States. Mov Disord 2013;28:311–8. [2] Martin I, Dawson VL, Dawson TM. Recent advances in the genetics of Parkinson’s disease. Annu Rev Genomics Hum Genet 2011;12:301–25. [3] Sundal C, Fujioka S, Uitti RJ, Wszolek ZK. Autosomal dominant Parkinson’s disease. Parkinsonism Relat Disord 2012;18(Suppl. 1):S7–S10. [4] Lopez G, Sidransky E. Autosomal recessive mutations in the development of Parkinson’s disease. Biomark Med 2010:713–21. [5] Simón-Sánchez J, Schulte C, Bras JM, Sharma M, Gibbs JR, Berg D, et al. Genome-wide association study reveals genetic risk underlying Parkinson’s disease. Nat Genet 2009;41:1308–12. [6] Maraganore DM, de Andrade M, Lesnick TG, Strain KJ, Farrer MJ, Rocca WA, et al. High-resolution whole-genome association study of Parkinson disease. Am J Hum Genet 2005;77:685–93. [7] Do CB, Tung JY, Dorfman E, Kiefer AK, Drabant EM, Francke U, et al. Web-based genome-wide association study identifies two novel loci and a substantial genetic component for Parkinson’s disease. PLoS Genet 2011;7:e1002141. [8] International Parkinson Disease Genomics Consortium, Nalls MA, Plagnol V, Hernandez DG, Sharma M, Sheerin UM, Saad M, et al. Imputation of sequence variants for identification of genetic risks for Parkinson’s disease: a metaanalysis of genome-wide association studies. Lancet 2011;377:641–9. [9] Saad M, Lesage S, Saint-Pierre A, Corvol JC, Zelenika D, Lambert JC, et al. Genome-wide association study confirms BST1 and suggests a locus on 12q24 as the risk loci for Parkinson’s disease in the European population. Hum Mol Genet 2011;20:615–27. [10] International Parkinson’s Disease Genomics Consortium (IPDGC); Wellcome Trust Case Control Consortium 2 (WTCCC2). A two-stage meta-analysis
[24]
[25] [26] [27]
[28]
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Khashayar Dashtipour Loma Linda University School of Medicine, Department of Neurology, 11370 Anderson, Suite B-100, Loma Linda, CA 92354, USA ⇑ Address: Department of Neurology/Movement Disorders, Loma Linda University School of Medicine, 11370 Anderson, Suite B-100, Loma Linda, CA 92354, USA. Tel.: +1 909 558 2120; fax: +1 909 558 5837. E-mail address: [email protected]
