Background Leucine-rich repeat kinase 2 (LRRK2) is known to harbor highly penetrant mutations linked to familial parkinsonism. However, its full polymorphic variability in relationship to Parkinson’s disease (PD) risk has not been systematically assessed. Methods We examined the frequency pathogenicity of 121 exonic LRRK2 variants in three ethnic series (Caucasian [N=12,590], Asian [N=2,338] and Arab-Berber [N=612]) consisting of 8,611 patients and 6,929 control subjects from 23 separate sites of the Genetic Epidemiology of Parkinson’s Disease Consortium. Findings Excluding carriers of previously known pathogenic mutations, new independent risk associations were found for polymorphic variants in Caucasian (p.M1646T, OR: 1.43, 95% CI: 1.15 – 1.78, P=0.0012) and Asian (p.A419V, OR: 2.27, 95% CI: 1.35 – 3.83, P=0.0011) populations. In addition, a protective haplotype was observed at >5% frequency (p.N551K-p.R1398H-p.K1423K) in the Caucasian and Asian series’, with a similar finding in the small Arab-Berber series that requires further study (combined 3-series OR: 0.82, 95% CI: 0.72 – 0.94, P=0.0043). Of the two previously reported Asian risk variants p.G2385R was found to be associated with disease (OR: 1.73, 95% CI: 1.20 – 2.49, P=0.0026) but no association was observed for p.R1628P (OR: 0.62, 95% CI: 0.36 – 1.07, P=0.087). Also in the Arab-Berber series, p.Y2189C showed potential evidence of risk association with PD (OR: 4.48, 95% CI: 1.33 – 15.09, P=0.012). Of note, two variants (p.I1371V and p.T2356I) which have been previously proposed as pathogenic were observed in patient and control subjects at the same frequency. Interpretation LRRK2 offers an example where multiple rare and common genetic variants in the same gene have independent effects on disease risk. Lrrk2, and the pathway in which it functions, is important in the etiology and pathogenesis of a greater proportion of patients with PD than previously believed. Funding The present study and original funding for the GEO-PD Consortium was supported by grants from Michael J. Fox Foundation. Studies at individual sites were supported by a number of funding agencies world-wide.

All living organisms have developed a highly conserved and regulatory system, the stress system, to cope with a broad spectrum of stressful stimuli that threaten, or are perceived as threatening, their dynamic equilibrium or homeostasis. This neuroendocrine system consists of the hypothalamic-pituitary-adrenal (HPA) axis and the locus caeruleus/norepinephrine-autonomic nervous system. In parallel with the evolution of the homeostasis and stress concepts from ancient Greek to modern medicine, significant advances in the field of neuroendocrinology have identified the physiologic biochemical effector molecules of the stress response. Glucocorticoids, the end-products of the HPA axis, play a fundamental role in the maintenance of both resting and stress-related homeostasis and, undoubtedly, influence the physiologic adaptive reaction of the organism against stressors. If the stress response is dysregulated in terms of magnitude and/or duration, homeostasis is turned into cacostasis with adverse effects on many vital physiologic functions, such as growth, development, metabolism, circulation, reproduction, immune response, cognition and behavior. A strong and/or long-lasting stressor may precipitate and/or cause many acute and chronic diseases. Moreover, stressors during pre-natal, post-natal or pubertal life may have a critical impact on our expressed genome. This review describes the central and peripheral components of the stress system, provides a comprehensive overview of the stress response, and discusses the role of glucocorticoids in a broad spectrum of stress-related diseases.

A number of studies have associated the S18Y polymorphic variant of UCH-L1 with protection from sporadic Parkinson's Disease (PD). The mechanism involved in this protective function is unknown, but has generally been assumed to be linked to the ubiquitin-proteasome system (UPS). In the current study, we have investigated the effects of overexpression of UCH-L1 and its variants, including S18Y, in neuronal cells. We find that S18Y, but not WT, UCH-L1 confers a specific antioxidant protective function when expressed at physiological levels in human neuroblastoma cells and primary cortical neurons. In contrast, neither WT nor S18Y UCH-L1 appear to directly impact the proteasome, although they both lead to stabilization of free ubiquitin. Lack of WT mouse UCH-L1 in neurons derived from gad mice led to a decrease of free ubiquitin, but no overall decrease in UPS function or enhanced sensitivity to oxidative stress. We conclude that the S18Y variant of UCH-L1 confers a novel antioxidant function that is not present in the WT form and that this function may underlie the protective effects of this variant in certain PD populations. Our results furthermore provide indirect evidence for the importance of oxidative stress as a pathogenetic factor in certain forms of sporadic PD.

Variants within the leucine-rich repeat kinase 2 gene are recognized as the most frequent genetic cause of Parkinson’s disease. Leucine-rich repeat kinase 2 variation related to susceptibility to disease displays many features that reflect the nature of complex late-onset sporadic disorders, such as Parkinson’s disease. The Genetic Epidemiology of Parkinson’s disease consortium recently performed the largest genetic association study for variants in the leucine-rich repeat kinase 2 gene across 23 different sites in 15 countries. Herein we detail the allele frequencies for the novel risk factors (p.A419V and p.M1646T) and the protective haplotype (p.N551K-R1398H-K1423K) reported in the original publication. Simple population allele frequencies can not only provide an insight into the clinical relevance of specific variants but also help genetically define patient groups. Establishing individual patient-based genomic susceptibility profiles incorporating both risk and protective factors will determine future diagnostic and treatment strategies.