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1.  Genomic investigation of α-Synuclein multiplication and parkinsonism 
Annals of neurology  2008;63(6):10.1002/ana.21380.
Objective
Copy number variation is a common polymorphic phenomenon within the human genome. While the majority of these events are non-deleterious they can also be highly pathogenic. Herein we characterize five families with parkinsonism that have been identified to harbor multiplication of the chromosomal 4q21 locus containing the α-synuclein gene (SNCA).
Methods
A methodological approach employing fluorescent in situ hybridization (FISH) and Affymetrix 250K SNP microarrays (CHIPs) was used to characterize the multiplication in each family and identify the genes encoded within the region. The telomeric and centromeric breakpoints of each family were further narrowed using semi-quantitative PCR with microsatellite markers and then screened for transposable repeat elements.
Results
The severity of clinical presentation is correlated with SNCA dosage and does not appear to be overtly effected by the presence of other genes in the multiplicated region. With the exception of the Lister kindred, in each family the multiplication event appears de novo. The type and position of Alu/LINE repeats are also different at each breakpoint. Microsatellite analysis demonstrates two genomic mechanisms are responsible for chromosome 4q21 multiplications, including both SNCA duplication and triplication.
Interpretation
SNCA dosage is responsible for parkinsonism, autonomic dysfunction and dementia observed within each family. We hypothesize dysregulated expression of wild-type α-synuclein results in parkinsonism and may explain the recent association of common SNCA variants in sporadic Parkinson’s disease. SNCA genomic duplication results from intra-allelic (segmental duplication) or inter-allelic recombination with unequal crossing-over, whereas both mechanisms appear to be required for genomic SNCA triplication.
doi:10.1002/ana.21380
PMCID: PMC3850281  PMID: 18571778
Parkinsonism; SNCA; Genomic multiplication; Alu repeat; Parkinson’s disease
2.  Alpha-synuclein overexpressing transgenic mice show internal organ pathology and autonomic deficits 
Neurobiology of Disease  2012;47(2):258-267.
While studying transgenic mice that overexpress human wildtype alpha-synuclein (Thy1-ASO, ASO) for typical brain alpha-synucleinopathy and central nervous system neuropathology, we observed progressive functional changes in the gastrointestinal and other peripheral organs. A more systematic study revealed that the gastrointestinal tract in ASO mice showed severe distension and blockage of the large intestine by 9–12 months of age. Functional assessments demonstrated a reduction in fecal water content and fecal pellet output, and increased whole gut transit time, in ASO mice compared to wildtype littermates, indicative of constipation, a symptom commonly reported by Parkinson's disease (PD) patients. Food intake was increased and body weight was decreased in 12 month old ASO mice, suggestive of metabolic abnormalities. Post-mortem histological analyses showed that human alpha-synuclein protein was robustly expressed in axonal fibers and in occasional cell bodies of the enteric nervous system, and in the heart of ASO mice. Accumulation of proteinase-K insoluble alpha-synuclein, reminiscent of neurodegenerative processes in PD was also observed. The functional and pathological changes we document here in ASO mice could relate to the autonomic deficits also seen in idiopathic and alpha-synuclein-mediated genetic forms of PD. These experimental data provide a foundation for therapeutic modeling of autonomic changes in PD and related alpha-synucleinopathies.
doi:10.1016/j.nbd.2012.04.009
PMCID: PMC3376017  PMID: 22549133
Alpha-synuclein; synucleinopathy; Parkinson's disease; constipation; gastrointestinal; autonomic; axonopathy
3.  Relationship of neighboring tissue and gliosis to α-synuclein pathology in a fetal transplant for Parkinson’s disease 
Background: Fetal transplantation for Parkinson disease (PD) had been considered a promising therapeutic strategy; however, reports of Lewy bodies (LBs) and Lewy neurites (LNs) in engrafted tissue adds to controversy surrounding this treatment for PD. Methods: The brain of a PD patient who had fetal transplantation 14 years before death was evaluated. The graft was studied with routine histologic methods, as well as immunohistochemistry for α-synuclein, neurofilament, synaptophysin and tyrosine hydroxylase (TH), as well as glial fibrillary acidic protein (GFAP) for astrocytes and ionized calcium-binding adaptor molecule 1 (IBA-1) for microglia. Results: On coronal sections of the brain, the graft extended from the putamen to the amygdala, abutting the anterior hippocampus. Microscopically, the graft consisted of neuron-rich and glia-rich portions. Neuron-rich portions, resembling a neuronal heterotopia, were located in the putamen, whereas the glia-rich portion was more ventral near the amygdala. LBs and LNs were detected in the ventral portion of the graft, especially that part of the graft within the amygdala. Areas with LBs and LNs also had astrogliosis and microgliosis. TH positive neurons were rare and their distribution did not overlap with LBs or LNs. Comments: LBs and LNs were detected in the transplanted tissue with α-synuclein immunohistochemistry. Unexpected outgrowth of the graft into the amygdala was accompanied by skewed distribution of LBs and gliosis, more abundant in the graft within the amygdala. The distribution of LBs within the graft may suggest the potential role of the local environment as well as gliosis in formation of α-synuclein pathology.
PMCID: PMC3560449  PMID: 23383381
Fetal transplantation; Parkinson disease (PD); therapy; α-synuclein pathology; gliosis
4.  Small Molecules Greatly Improve Conversion of Human-Induced Pluripotent Stem Cells to the Neuronal Lineage 
Stem Cells International  2012;2012:140427.
Efficient in vitro differentiation into specific cell types is more important than ever after the breakthrough in nuclear reprogramming of somatic cells and its potential for disease modeling and drug screening. Key success factors for neuronal differentiation are the yield of desired neuronal marker expression, reproducibility, length, and cost. Three main neuronal differentiation approaches are stromal-induced neuronal differentiation, embryoid body (EB) differentiation, and direct neuronal differentiation. Here, we describe our neurodifferentiation protocol using small molecules that very efficiently promote neural induction in a 5-stage EB protocol from six induced pluripotent stem cells (iPSC) lines from patients with Parkinson's disease and controls. This protocol generates neural precursors using Dorsomorphin and SB431542 and further maturation into dopaminergic neurons by replacing sonic hedgehog with purmorphamine or smoothened agonist. The advantage of this approach is that all patient-specific iPSC lines tested in this study were successfully and consistently coaxed into the neural lineage.
doi:10.1155/2012/140427
PMCID: PMC3339118  PMID: 22567022
5.  The promise of stem cells in Parkinson disease 
Neurotransplantation as a treatment for Parkinson disease reached the stage of human trials over 15 years ago, but the field, which is still in its infancy, has encountered a number of roadblocks since then, both political and scientific. With hope that stem cells may be used as a new source of dopaminergic neurons to replace the degenerating nerve cells in Parkinson disease looming, it is critical that we learn from the past as we work toward achieving new milestones aimed at making this new therapeutic strategy a reality. One of those milestones, which is an important translational step in the development of stem cell technology and the subject of a report in this issue of the JCI, involves transplanting new dopaminergic cell lines to a primate model of Parkinson disease.
doi:10.1172/JCI200524012
PMCID: PMC539212  PMID: 15630437
6.  Genetic Modification of the Association of Paraquat and Parkinson’s Disease 
Paraquat is one of the most widely used herbicides worldwide. It produces a Parkinson’s disease (PD) model in rodents through redox cycling and oxidative stress (OS) and is associated with PD risk in humans. Glutathione transferases provide cellular protection against OS and could potentially modulate paraquat toxicity. We investigated PD risk associated with paraquat use in individuals with homozygous deletions of the genes encoding glutathione S-transferase M1 (GSTM1) or T1 (GSTT1). Eighty-seven PD subjects and 343 matched controls were recruited from the Agricultural Health Study, a study of licensed pesticide applicators and spouses in Iowa and North Carolina. PD was confirmed by in-person examination. Paraquat use and covariates were determined by interview. We genotyped subjects for homozygous deletions of GSTM1 (GSTM1*0) and GSTT1 (GSTT1*0) and tested interaction between paraquat use and genotype using logistic regression. Two hundred and twenty-three (52%) subjects had GSTM1*0, 95 (22%) had GSTT1*0, and 73 (17%; all men) used paraquat. After adjustment for potential confounders, there was no interaction with GSTM1. In contrast, GSTT1 genotype significantly modified the association between paraquat and PD. In men with functional GSTT1, the odds ratio (OR) for association of PD with paraquat use was 1.5 (95% confidence interval [CI]: 0.6–3.6); in men with GSTT1*0, the OR was 11.1 (95% CI: 3.0–44.6; P interaction: 0.027). Although replication is needed, our results suggest that PD risk from paraquat exposure might be particularly high in individuals lacking GSTT1. GSTT1*0 is common and could potentially identify a large subpopulation at high risk of PD from oxidative stressors such as paraquat.
doi:10.1002/mds.25216
PMCID: PMC3572192  PMID: 23045187
Parkinson’s disease; paraquat; glutathione transferase; pesticide; gene-environment interaction
7.  The neurophysiology and effect of deep brain stimulation in a human with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) -induced parkinsonism 
Journal of neurosurgery  2009;110(2):234-238.
Parkinsonism caused by MPTP exposure was first identified in intravenous drug users. The neurotoxicant has since been used extensively in nonhuman primates to induce an experimental model of Parkinson’s disease. We examined the intraoperative physiology and the efficacy of subthalamic nucleus deep brain stimulation (DBS) in 1 of only 4 known living humans with MPTP-induced parkinsonism. The physiologic recordings were consistent with recordings from MPTP-treated primates and humans with Parkinson’s disease, thus further validating the MPTP model for the study of the neurophysiology of the nigrostriatal dopaminergic deficit in Parkinson’s disease. Furthermore, DBS offered significant clinical improvement in this patient similar to that seen in idiopathic Parkinson’s disease. This unique case has important implications for translational research that employs the MPTP-primate model for symptomatic therapy in Parkinson’s disease.
doi:10.3171/2008.8.JNS08882
PMCID: PMC2908499  PMID: 19099380
Parkinson’s disease; toxin; parkinsonism; Parkinsonian; deep brain stimulation; subthalamic nucleus; physiology
8.  A Whole Genome Survey of Coding SNPs Reveals a Reproducible Pathway Determinant of Parkinson Disease 
Human mutation  2009;30(2):228-238.
It is quickly becoming apparent that situating human variation in a pathway context is crucial to understanding its phenotypic significance. Towards this end, we have developed a general method for finding pathways associated with traits which controls for pathway size. We have applied this method to a new whole genome survey of coding SNP variation in 187 patients afflicted with Parkinson disease (PD) and 187 controls. We show that our dataset provides an independent replication of the axon guidance association recently reported by Lesnick et al., and also indicates that variation in the ubiquitin mediated proteolysis and T-cell receptor signaling pathways may predict PD susceptibility. Given this result, it is reasonable to hypothesize that pathway associations are more replicable than individual SNP associations in whole genome association studies. However, this hypothesis is complicated by a detailed comparison of our dataset to the second recent PD association study by Fung et al. Surprisingly, we find that the axon guidance pathway does not rank at the very top of the Fung dataset after controlling for pathway size. More generally, in comparing the studies we find that SNP frequencies replicate well despite technologically different assays, but that both SNP and pathway associations are globally uncorrelated across studies. We thus have a situation in which an association between axon guidance pathway variation and PD has been found in two out of three studies. We conclude by relating this seeming inconsistency to the molecular heterogeneity of PD, and suggest future analyses which may resolve such discrepancies.
doi:10.1002/humu.20840
PMCID: PMC2793088  PMID: 18853455
whole genome association; Parkinson’s disease; PD; Parkinson; pathway association; axon guidance; candidate pathways
9.  Elevated Alpha-Synuclein Impairs Innate Immune Cell Function and Provides a Potential Peripheral Biomarker for Parkinson's Disease 
PLoS ONE  2013;8(8):e71634.
Alpha-synuclein protein is strongly implicated in the pathogenesis Parkinson's disease. Increased expression of α-synuclein due to genetic multiplication or point mutations leads to early onset disease. While α-synuclein is known to modulate membrane vesicle dynamics, it is not clear if this activity is involved in the pathogenic process or if measurable physiological effects of α-synuclein over-expression or mutation exist in vivo. Macrophages and microglia isolated from BAC α-synuclein transgenic mice, which overexpress α-synuclein under regulation of its own promoter, express α-synuclein and exhibit impaired cytokine release and phagocytosis. These processes were affected in vivo as well, both in peritoneal macrophages and microglia in the CNS. Extending these findings to humans, we found similar results with monocytes and fibroblasts isolated from idiopathic or familial Parkinson's disease patients compared to age-matched controls. In summary, this paper provides 1) a new animal model to measure α-synuclein dysfunction; 2) a cellular system to measure synchronized mobilization of α-synuclein and its functional interactions; 3) observations regarding a potential role for innate immune cell function in the development and progression of Parkinson's disease and other human synucleinopathies; 4) putative peripheral biomarkers to study and track these processes in human subjects. While altered neuronal function is a primary issue in PD, the widespread consequence of abnormal α-synuclein expression in other cell types, including immune cells, could play an important role in the neurodegenerative progression of PD and other synucleinopathies. Moreover, increased α-synuclein and altered phagocytosis may provide a useful biomarker for human PD.
doi:10.1371/journal.pone.0071634
PMCID: PMC3751933  PMID: 24058406
10.  The selective κ-opioid receptor agonist U50,488 reduces L-dopa-induced dyskinesias but worsens parkinsonism in MPTP-treated primates 
Experimental neurology  2007;205(1):101-107.
Several lines of evidence demonstrate that the striatal enkephalinergic system may be involved in the development of LIDs. Preproenkephalin-B (PPE-B) transcript levels are elevated with LIDs and there are also declines in κ- and other opioid receptors in different regions of the basal ganglia. If reduced κ-opioid receptors are linked to LIDs, it is possible that drugs that stimulate this subtype may decrease dyskinesias. We therefore initiated experiments to investigate the effect of κ-opioid receptor activation on LIDs. We first tested the selective κ-agonist U50,488 in rats with unilateral lesions of the nigrostriatal pathway. Chronic L-dopa treatment induced abnormal involuntary movements, including axial, orolingual and forelimb dyskinesias contralateral to the lesion. U50,488 administration prior to L-dopa treatment reduced these movements by 70%, suggesting that U50,488 has potential as an anti-dyskinetic treatment. We next tested its effect in a parkinsonian nonhuman primate model, which offers the advantage that parkinsonism and LIDs can clearly be differentiated and that the dyskinesias are similar to those in parkinsonian patients. 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-lesioned monkeys were treated with L-dopa (5 mg/kg, p.o.) twice daily for 3 weeks to induce dyskinesias. As in the rodent model, U50,488 (0.1–1.0 mg/kg, i.m.) decreased LIDs in a dose-dependent fashion. However the anti-parkinsonian effect of L-dopa was similarly reduced, and side effects developed, including sedation and vomiting. These data suggest that κ-opioid agonists such as U50,488 may not be clinically useful antidyskinetic agents because they also reverse the anti-parkinsonian effect of L-dopa.
doi:10.1016/j.expneurol.2007.01.024
PMCID: PMC2001245  PMID: 17335811
dyskinesia; rat; monkey; U50; 488; Parkinson’s disease
11.  Solvent Exposures and Parkinson’s Disease Risk in Twins 
Annals of Neurology  2011;71(6):776-784.
Objective
Several case reports have linked solvent exposure to Parkinson’s disease (PD), but few studies have assessed associations with specific agents using an analytic epidemiologic design. We tested the hypothesis that exposure to specific solvents is associated with PD risk using a discordant twin pair design.
Methods
99 twin pairs discordant for PD ascertained from the National Academy of Science/National Research Council (NAS/NRC) World War II Veteran Twins Cohort were interviewed regarding lifetime occupations and hobbies using detailed job-task-specific questionnaires. Exposures to 6 specific solvents selected a priori were estimated by expert raters unaware of case status.
Results
Ever exposure to trichloroethylene (TCE) was associated with significantly increased risk of PD (OR 6.1, 95%CI 1.2 – 33; p = 0.034), and exposure to perchloroethylene (PERC) and carbon tetrachloride (CCl4) tended toward significance (respectively: OR 10.5, 95%CI 0.97-113, p = 0.053; OR 2.3, 95%CI 0.9-6.1, p = 0.088). Results were similar for estimates of exposure duration and cumulative lifetime exposure.
Interpretation
Exposure to specific solvents may increase risk of PD. TCE is the most common organic contaminant in groundwater, and PERC and CCl4 are also ubiquitous in the environment. Our findings require replication in other populations with well-characterized exposures, but the potential public health implications are substantial.
doi:10.1002/ana.22629
PMCID: PMC3366287  PMID: 22083847
12.  Head Injury, Alpha-Synuclein Rep1 and Parkinson’s Disease 
Annals of Neurology  2012;71(1):40-48.
Objective
To test the hypothesis that variability in SNCA Rep1, a polymorphic dinucleotide microsatellite in the promoter region of the gene encoding α-synuclein, modifies the association between head injury and Parkinson’s disease (PD) risk.
Methods
Participants in Farming and Movement Evaluation (FAME) and Study of Environmental Association and Risk of Parkinsonism using Case-Control Historical Interviews (SEARCH), two independent case-control studies, were genotyped for Rep1 and interviewed regarding head injuries with loss of consciousness or concussion prior to PD diagnosis. Logistic regression modeling adjusted for potential confounding variables and tested interaction between Rep1 genotype and head injury.
Results
Consistent with prior reports, relative to medium-length Rep1, short Rep1 genotype was associated with reduced PD risk (pooled odds ratio (OR) 0.7, 95% confidence interval (CI) 0.5-0.9), and long Rep1 with increased risk (pooled OR 1.4, 95%CI 0.95-2.2). Overall, head injury was not significantly associated with PD (pooled OR 1.3, 95%CI 0.9-1.8). However, head injury was strongly associated with PD in those with long Rep1 (FAME OR 5.4, 95%CI 1.5-19; SEARCH OR 2.3, 95%CI 0.6-9.2; pooled OR 3.5, 95%CI 1.4-9.2, p-interaction 0.02). Individuals with both head injury and long Rep1 were diagnosed 4.9 years earlier than those with neither risk factor (p = 0.03).
Interpretation
While head injury alone was not associated with PD risk, our data suggest head injury may initiate and/or accelerate neurodegeneration when levels of synuclein are high, as in those with Rep1 expansion. Given the high population frequency of head injury, independent verification of these results is essential.
doi:10.1002/ana.22499
PMCID: PMC3270814  PMID: 22275250
13.  SNCA Triplication Parkinson's Patient's iPSC-derived DA Neurons Accumulate α-Synuclein and Are Susceptible to Oxidative Stress 
PLoS ONE  2011;6(11):e26159.
Parkinson's disease (PD) is an incurable age-related neurodegenerative disorder affecting both the central and peripheral nervous systems. Although common, the etiology of PD remains poorly understood. Genetic studies infer that the disease results from a complex interaction between genetics and environment and there is growing evidence that PD may represent a constellation of diseases with overlapping yet distinct underlying mechanisms. Novel clinical approaches will require a better understanding of the mechanisms at work within an individual as well as methods to identify the specific array of mechanisms that have contributed to the disease. Induced pluripotent stem cell (iPSC) strategies provide an opportunity to directly study the affected neuronal subtypes in a given patient. Here we report the generation of iPSC-derived midbrain dopaminergic neurons from a patient with a triplication in the α-synuclein gene (SNCA). We observed that the iPSCs readily differentiated into functional neurons. Importantly, the PD-affected line exhibited disease-related phenotypes in culture: accumulation of α-synuclein, inherent overexpression of markers of oxidative stress, and sensitivity to peroxide induced oxidative stress. These findings show that the dominantly-acting PD mutation is intrinsically capable of perturbing normal cell function in culture and confirm that these features reflect, at least in part, a cell autonomous disease process that is independent of exposure to the entire complexity of the diseased brain.
doi:10.1371/journal.pone.0026159
PMCID: PMC3217921  PMID: 22110584
14.  Web-Based Genome-Wide Association Study Identifies Two Novel Loci and a Substantial Genetic Component for Parkinson's Disease 
PLoS Genetics  2011;7(6):e1002141.
Although the causes of Parkinson's disease (PD) are thought to be primarily environmental, recent studies suggest that a number of genes influence susceptibility. Using targeted case recruitment and online survey instruments, we conducted the largest case-control genome-wide association study (GWAS) of PD based on a single collection of individuals to date (3,426 cases and 29,624 controls). We discovered two novel, genome-wide significant associations with PD–rs6812193 near SCARB2 (, ) and rs11868035 near SREBF1/RAI1 (, )—both replicated in an independent cohort. We also replicated 20 previously discovered genetic associations (including LRRK2, GBA, SNCA, MAPT, GAK, and the HLA region), providing support for our novel study design. Relying on a recently proposed method based on genome-wide sharing estimates between distantly related individuals, we estimated the heritability of PD to be at least 0.27. Finally, using sparse regression techniques, we constructed predictive models that account for 6%–7% of the total variance in liability and that suggest the presence of true associations just beyond genome-wide significance, as confirmed through both internal and external cross-validation. These results indicate a substantial, but by no means total, contribution of genetics underlying susceptibility to both early-onset and late-onset PD, suggesting that, despite the novel associations discovered here and elsewhere, the majority of the genetic component for Parkinson's disease remains to be discovered.
Author Summary
We conducted a large genome-wide association study (GWAS) of Parkinson's disease (PD) with over 3,400 cases and 29,000 controls (the largest single PD GWAS cohort to date). We report two novel genetic associations and replicate a total of twenty previously described associations, showing that there are now many solid genetic factors underlying PD. We also estimate that genetic factors explain at least one-fourth of the variation in PD liability, of which currently discovered factors only explain a small fraction (6%–7%). Together, these results expand the set of genetic factors discovered to date and imply that many more associations remain to be found. Unlike traditional studies, participation in this study took place completely online, using a collection of cases recruited primarily via PD mailing lists and controls derived from the customer base of the personal genetics company 23andMe. Our study thus illustrates the ability of web-based methods for enrollment and data collection to yield new scientific insights into the etiology of disease, and it demonstrates the power and reliability of self-reported data for studying the genetics of Parkinson's disease.
doi:10.1371/journal.pgen.1002141
PMCID: PMC3121750  PMID: 21738487
15.  Rotenone, Paraquat, and Parkinson’s Disease 
Environmental Health Perspectives  2011;119(6):866-872.
Background
Mitochondrial dysfunction and oxidative stress are pathophysiologic mechanisms implicated in experimental models and genetic forms of Parkinson’s disease (PD). Certain pesticides may affect these mechanisms, but no pesticide has been definitively associated with PD in humans.
Objectives
Our goal was to determine whether pesticides that cause mitochondrial dysfunction or oxidative stress are associated with PD or clinical features of parkinsonism in humans.
Methods
We assessed lifetime use of pesticides selected by mechanism in a case–control study nested in the Agricultural Health Study (AHS). PD was diagnosed by movement disorders specialists. Controls were a stratified random sample of all AHS participants frequency-matched to cases by age, sex, and state at approximately three controls: one case.
Results
In 110 PD cases and 358 controls, PD was associated with use of a group of pesticides that inhibit mitochondrial complex I [odds ratio (OR) = 1.7; 95% confidence interval (CI), 1.0–2.8] including rotenone (OR = 2.5; 95% CI, 1.3–4.7) and with use of a group of pesticides that cause oxidative stress (OR = 2.0; 95% CI, 1.2–3.6), including paraquat (OR = 2.5; 95% CI, 1.4–4.7).
Conclusions
PD was positively associated with two groups of pesticides defined by mechanisms implicated experimentally—those that impair mitochondrial function and those that increase oxidative stress—supporting a role for these mechanisms in PD pathophysiology.
doi:10.1289/ehp.1002839
PMCID: PMC3114824  PMID: 21269927
aging; agricultural epidemiology; environmental epidemiology; epidemiology; fungicides; herbicides; insecticides; persistent organic pollutants; pesticides
16.  Neurology 
Western Journal of Medicine  1987;146(3):351.
PMCID: PMC1307284  PMID: 18750169

Results 1-16 (16)