Paraquat (PQ) is a putative risk factor for the development of sporadic Parkinson\'s disease. To model a possible genetic basis for individual differences in susceptibility to exposure to PQ, we recently examined the effects of paraquat on tyrosine hydroxylase (TH)-containing neurons in the substantia nigra pars compacta (SNc) of six members of the BXD family of mice (n = 2-6 per strain). We injected males with 5 mg/kg paraquat weekly three times. The density of TH+ neurons counted by immunocytochemistry at 200x in eight or more sections through the SNc is reduced in five of the six strains relative to control (N = 4 ± 2 mice per strain). TH+ loss ranged from 0 to 20% with an SEM of 1%. The heritability was estimated using standard ANOVA and jackknife resampling and is 0.37 ± 0.05 in untreated animals and 0.47 ± 0.04 in treated animals. These results demonstrate genetic modulation and GxE variation in susceptibility to PQ exposure and the loss of TH staining in the substantia nigra.

The fact that Parkinson\'s disease (PD) pathologies are well advanced in most PD patients by the time of clinical elucidation attests to the importance of early diagnosis. Our attempt to achieve this has capitalized on our previous finding that GM1 ganglioside is expressed at subnormal levels in virtually all tissues of sporadic PD (sPD) patients including blood cells. GM1 is present in most vertebrate cells, is especially abundant in neurons where it was shown essential for their effective functioning and long term viability. We have utilized peripheral blood mononuclear cells (PBMCs) which, despite their low GM1, we found to be significantly lower in sPD patients compared to age-matched healthy controls. To quantify GM1 (and GD1a) we used high performance thin-layer chromatography combined with cholera toxin B linked to horseradish peroxidase, followed by densitometric quantification. GM1 was also deficient in PBMCs from PD patients with mutations in the glucocerebrosidase gene (PD-GBA), apparently even lower than in sPD. Reasons are given why we believe these results obtained with patients manifesting fully developed PD will apply as well to PD patients in preclinical stages-a topic for future study. We also suggest that these findings point to a potential disease altering therapy for PD once the early diagnosis is established.

Sporadic Parkinson\'s disease (sPD) and sporadic amyotrophic lateral sclerosis (sALS) are neurodegenerative diseases characterized by progressive and selective neuron death, with some genetic similarities. In order to investigate the genetic risk factors common to both sPD and sALS, we carried out a screen of risk alleles for sALS and related loci in 530 sPD patients and 530 controls from the Han population of Mainland China (HPMC). We selected 27 single-nucleotide polymorphisms in 10 candidate genes associated with sALS, and we performed allelotyping and genotyping to determine their frequencies in the study population as well as bioinformatics analysis to assess their functional significance in these diseases. The minor alleles of rs17115303 in DAB adaptor protein 1 (DAB1) gene and rs6030462 in protein tyrosine phosphatase receptor type T (PTPRT) gene were correlated with increased risk of both sPD and sALS. Polymorphisms of rs17115303 and rs6030462 were associated with alterations in transcription factor binding sites, secondary structures, long non-coding RNA interactions, and nervous system regulatory networks; these changes involved biological processes associated with neural cell development, differentiation, neurogenesis, migration, axonogenesis, cell adhesion, and metabolism of phosphate-containing compounds. Thus, variants of DAB1 gene (rs17115303) and PTPRT gene (rs6030462) are risk factors common to sPD and sALS in the HPMC. These findings provide insight into the molecular pathogenesis of both diseases and can serve as a basis for the development of targeted therapies.

Many clinical symptoms of sporadic Parkinson\'s disease (sPD) cannot be completely explained by a lesion of the simple typical extrapyramidal circuit between the striatum and substantia nigra. Therefore, this study aimed to explore the new potential damaged pathogenesis of other brain regions associated with the multiple and complex clinical symptoms of sPD through magnetic resonance imaging (MRI). A total of 65 patients with mid-stage sPD and 35 healthy controls were recruited in this study. Cortical structural connectivity was assessed by seed-based analysis using the vertex-based morphology of MRI. Seven different clusters in the brain regions of cortical thickness thinning derived from the regression analysis using brain size as covariates between sPD and control were selected as seeds. Results showed that the significant alteration of cortical structural connectivity mainly occurred in the bilateral frontal orbital, opercular, triangular, precentral, rectus, supplementary-motor, temporal pole, angular, Heschl, parietal, supramarginal, postcentral, precuneus, occipital, lingual, cuneus, Rolandic-opercular, cingulum, parahippocampal, calcarine, olfactory, insula, paracentral-lobule, and fusiform regions at the mid-stage of sPD. These findings suggested that the extensive alteration of cortical structural connectivity is one of possible pathogenesis resulting in the multiple and complex clinical symptoms in sPD.

Recent investigations demonstrated that genetic factors might play an important role in sporadic Parkinson\'s disease (sPD). To clarify the specific loci susceptibility to sPD, we analyze the relationship between 30 candidate single nucleotide polymorphisms (SNPs) and sPD in the population of Han ancestry from Chinese mainland (HACM) by using genome-wide association study, sequenom massARRAY, DNA sequence, and biological information analysis. Results showed that the subjects carrying the T allele of rs863108 and rs28499371 exhibited a decreased risk for sPD. The subjects carrying the T allele of rs80315856 exhibited an increased risk for sPD. The A/T genotype of rs863108 and the C/T genotype of rs28499371 were a potential increased risk for sPD, and the G/T genotype of rs80315856 and T/T genotype of rs2270568 were a potential decreased risk for sPD. The minor allele frequency (MAF) of rs80315856 and rs2270568 was higher in sPD. The T allele of rs80315856 and rs2270568 might be a risk locus for sPD. Our data suggested that the alteration of these SNPs might play some roles through changing/affecting LINC01524/LOC105372666, DMRT2/SMARCA2, PLEKHN1, and FLJ23172/FNDC3B genes in the pathogenesis of sPD.

Paraquat (PQ) is an herbicide used in many countries, including the United States. It is also implicated as a risk factor for sporadic Parkinson\'s disease, especially in those living in agricultural areas and drinking well water. Studies linking PQ to sporadic Parkinson\'s disease are not consistent however and there appears to be interindividual differential susceptibility. One likely reason is genetically based differential susceptibility to paraquat neurotoxicity in subpopulations. To address this issue, we tested the effects of paraquat in a genetic reference population of mice (the BXD recombinant inbred strain family). In our earlier work, we showed that in genetically susceptible mice, paraquat increases iron in the ventral midbrain, the area containing the substantia nigra. Our hypothesis is that genetic variability contributes to diverse PQ-related susceptibility and iron concentration. To test this hypothesis, we treated male mice from 28 to 39 BXD strains plus the parental strains with 1 of 3 doses of paraquat, 1, 5, and 10 mg/kg 3 times on a weekly basis. At the end of the treatment period, we analyzed the ventral midbrain for concentrations of iron, copper, and zinc, also we measured the concentration of paraquat in cerebellum, and proinflammatory cytokines in serum and cerebellum. The effect on paraquat-treated mice with 5 mg/kg and principal component analysis of iron showed suggestive quantitative trait loci on chromosome 5. Overall, our results suggest that gene Prkag2 and related networks may serve as potential targets against paraquat toxicity and demonstrate the utility of genetically diverse mouse models for the study of complex human toxicity.

Following Braak\'s hypothesis on the infectious pathogenesis of sporadic Parkinson\'s disease (sPD), several bacteria and viruses have been investigated as likely culprits. Recent research has focused on neuroinvasive influenza A viruses (IAV), whereas a genetic link between sPD and tuberculosis has arisen in LRRK2 - dependent maturation of the phagosome. An integrative, outside - in, multi - hit hypothesis is presented here, where (a) mycobacterial immunomodulation creates a phagocyte niche along with cytokine mediated, site specific (i.e. the gut) alterations of both immunity and the microbiome, (b) copper modulating IAVs gain latency in and control over phagocytes and their phenotypes, (c) gain access to the central nervous system (CNS) via the olfactory and vagus nerves in subsequent infection cycles, (d) induce indolent neuroinflammation characterized by perturbed intraneuronal copper compartmentalization and (e) produce α - synuclein (aSyn) pathology at least in part via copper - induced aggregation and misfolding as well as potential synergy with other underlying, corroborating factors (either genetic or acquired) contributing to dopaminergic neurodegeneration. This hypothesis explores recently arisen evidence for each step of this process, as well as pre-existing, yet unexplored overlapping pathophysiological characteristics of sPD with mycobacterial and IAV infections. The implications of this proposed pathogenic model extend both in sPD research (i.e. determining non - tuberculous mycobacteria as the first hit organism, inactivating IAV - induced copper hijacking), as well as therapeutics.

Parkinson\'s disease (PD) is the most common cause of movement disorders and is characterized by the progressive loss of dopaminergic neurons in the substantia nigra. It is increasingly recognized as a complex group of disorders presenting widely heterogeneous symptoms and pathology. With the exception of the rare monogenic forms, the majority of PD cases result from an interaction between multiple genetic and environmental risk factors. The search for these risk factors and the development of preclinical animal models are in progress, aiming to provide mechanistic insights into the pathogenesis of PD. This review summarizes the studies that capitalize on modeling sporadic (i.e., nonfamilial) PD using Drosophila melanogaster and discusses their methodologies, new findings, and future perspectives.

Parkinson\'s disease (PD) is a neurodegenerative disorder characterized by the progressive degeneration of midbrain neurons (MBNs). Recent evidence suggests contribution of the adaptive immune system in PD. Here, we show a role for human T lymphocytes as cell death inducers of induced pluripotent stem cell (iPSC)-derived MBNs in sporadic PD. Higher Th17 frequencies were found in the blood of PD patients and increased numbers of T lymphocytes were detected in postmortem PD brain tissues. We modeled this finding using autologous co-cultures of activated T lymphocytes and iPSC-derived MBNs of sporadic PD patients and controls. After co-culture with T lymphocytes or the addition of IL-17, PD iPSC-derived MBNs underwent increased neuronal death driven by upregulation of IL-17 receptor (IL-17R) and NFκB activation. Blockage of IL-17 or IL-17R, or the addition of the FDA-approved anti-IL-17 antibody, secukinumab, rescued the neuronal death. Our findings indicate a critical role for IL-17-producing T lymphocytes in sporadic PD.

The worldwide spread of Parkinson\'s disease (PD) calls for sensitive and specific measures enabling its early (or, ideally, preclinical) detection. Here, we use language measures revealing deficits in PD to explore whether similar disturbances are present in asymptomatic individuals at risk for the disease.
We administered executive, semantic, verb-production, and syntactic tasks to sporadic PD patients, genetic PD patients with PARK2 (parkin) or LRRK2 (dardarin) mutation, asymptomatic first-degree relatives of the latter with similar mutations, and socio-demographically matched controls. Moreover, to detect sui generis language disturbances, we ran analysis of covariance tests using executive functions as covariate.
The two clinical groups showed impairments in all measures, most of which survived covariation with executive functions. However, the key finding concerned asymptomatic mutation carriers. While these subjects showed intact executive, semantic, and action-verb production skills, they evinced deficits in a syntactic test with minimal working memory load.
We propose that this sui generis disturbance may constitute a prodromal sign anticipating eventual development of PD. Moreover, our results suggest that mutations on specific genes (PARK2 and LRRK2) compromising basal ganglia functioning may be subtly related to language-processing mechanisms. (JINS, 2017, 23, 150-158).