Pathogenesis Of PD Research Articles

Redox Control of the Survival of Healthy and Diseased Cells

Abstract Cellular redox homeostasis is the first line of defense against diverse stimuli and is crucial for various biological processes. Reactive oxygen species (ROS), byproducts of numerous cellular events, may serve in turn as signaling molecules to regulate cellular processes such as proliferation, differentiation, and apoptosis. However, when overproduced ROS fail to be scavenged by the antioxidant system, they may damage cellular components, giving rise to senescent, degenerative, or fatal lesions in cells. Accordingly, this review not only covers general mechanisms of ROS production under different conditions, but also focuses on various types of ROS-involved diseases, including atherosclerosis, ischemia/reperfusion injury, diabetes mellitus, neurodegenerative diseases, and cancer. In addition, potentially therapeutic agents and approaches are reviewed in a relatively comprehensive manner. However, due to the complexity of ROS and their cellular impacts, we believe that the goal to design more effective approaches or agents may require a better understanding of mechanisms of ROS production, particularly their multifaceted impacts in disease at biochemical, molecular, genetic, and epigenetic levels. Thus, it requires additional tools of omics in systems biology to achieve such a goal. Antioxid. Redox Signal. 15, 2867-2908.

ASICs mediate the modulatory effect by paeoniflorin on alpha-synuclein autophagic degradation

Acid-sensing ion channels (ASICs) are ligand-gated cation channels that respond to acidic stimuli. They are expressed throughout the mammalian nervous system. Complex subunit combinations and lack of specific blockers of native receptors result in the difficulty of resolving the functions of ASICs. In this study, we showed that rat pheochromocytoma cells (PC12 cells) functionally express ASICs with the activity of endogenous proton-gated conductance. PF is the principal active ingredient extracted from the root of Paeoniae alba, a Chinese herb commonly used to treat neurodegenerative disorders, especially PD. It was found that PF significantly up regulated the expression of LC3-II, which is specifically associated with autophagic vacuole membranes. PF also reduced the MPP + and acidosis-induced accumulation of α-synuclein, the major component of Lewy bodies. Moreover, PF was highly efficacious in modulating ASICs activity and protein expression. In addition, the data showed that PF was able to protect PC12 cells against MPP + and acidosis-induced cytotoxicity. In summary, these findings demonstrate for the first time that PF could enhance the autophagic degradation of α-synuclein by regulating the expression and activity of ASICs and thus produces protective effects against cytotoxicity. It also offers the experimental evidence for the potential role of ASICs in the pathogenesis of PD.

Time course of changes in rotational behavior and DA metabolism in rats lesioned unilaterally with the selective proteasome inhibitor lactacystin

A growing body of evidence suggests that proteasomal dysfunction may play an important role in the pathogenesis of PD. The aim of our study was to examine the effect of unilateral administration of lactacystin, a selective proteasome inhibitor, on rotational behavior and striatal and nigral metabolism of dopamine (DA). Male Wistar rats were used for the study. The animals were injected unilaterally with a single dose of lactacystin (2.5 μg/2 μl) into the substantia nigra (SN) pars compacta. After injection, the rats were examined for spontaneous and apomorphine (0.25 mg/kg)induced rotational behavior in rotameter bowls throughout 60 min. All the testing was done on days 1, 4, 7, 14 and 21 after lactacystin administration. The animals were killed by decapitation on post-lesional days 1, 4, 7 and 21. The levels of DA and its metabolites were assayed in striatal and nigral homogenates using an HPLC method. Behavioral studies showed that the lactacystin-lesioned rats, but not the shamoperated animals, displayed a strong spontaneous circling behavior contralateral to the lesioned side on the 1 and 4 day after lactacystin treatment. This effect disappeared 1 week after the lesion. After apomorfine treatment on day 7, 14 and 21 days after surgery, no contralateral turning was observed in the lesioned rats. Biochemical studies demonstrated that lactacystin evoked a progressive loss in DA and its metabolites in the ipsilateral striatum and SN compared to the ipsilateral striatum of the sham-operated rats. The decreases started on the 7 day after lesion except for the drop in the nigral DA level which began already on the 4 day after surgery. After 21 days, the decline in DA level exceed 90% both in the striatum and SN. As regards DA catabolism, lactacystin evoked a progressive acceleration of MAO-dependent oxidative DA catabolism (DOPAC/DA), COMT-dependent Omethylation (3-MT/DA) and total DA catabolism (HVA/DA), both in the ipsilateral striatum and SN. The present study shows that lactacystin produces biochemical changes characteristic of degeneration of the DA system, namely a robust progressive decrease in DA level and an increase in DA catabolism. However, the presence of spontaneous contralateral rotations on the first few days after lesion indicates that other, probably non-DA mechanisms may play a role in this phenomenon. On the other hand, the lack of contralateral rotations after apomorphine up to three weeks after surgery suggests that the lactacystin-induced dramatic loss of striatal DA does not lead to supersensitivity of the striatal postsynaptic DA receptors.

Parkinson's disease dementia and potential therapeutic strategies.

Dementia in Parkinson's disease (PD-D) has only been acknowledged in the recent three decades, but research in this field has accelerated. The purpose of this review was to discuss advances in PD-D regarding biomarker correlates and potential therapeutic targets. Attention and executive dysfunction, memory deficits that improve with cueing, and visual hallucinations are characteristic in PD-D. PD-D dramatically increases the disability and misery of the disease. Current treatment for PD-D is symptomatic, modest, and only transiently effective. There is wide agreement that more effective treatment is needed, but this will require more knowledge about PD-D pathophysiology. Advances in the pathogenesis of PD have focused on the substantia nigra, which is the location from where the pathophysiology of motor symptoms primarily arises in initial stages. In contradistinction, pathology studies have suggested that cognitive decline correlates with cortical and subcortical-cortical projection pathway abnormalities. There is evidence that substantia nigra mechanisms, including protein aggregation of α-synuclein (e.g., Lewy bodies) may also play a role in cortical neuron degeneration. Other different mechanisms, such as Alzheimer's disease pathology (e.g., Aβ aggregation) may be operant for PD-D. Biomarkers of various types are being proposed for the study of PD-D as well as for objective measures of PD-D prediction and progression. Therapeutic targets are currently derived mostly from general PD neurodegeneration research rather than cortical PD neurodegeneration per se. Protein aggregation, genes that are associated with PD, oxidative stress, inflammation, and trophic factors constitute the major classes of therapeutic targets for PD-D. More research is needed on the specific aspects of cortical dysfunction and degeneration that create PD-D.

Prolonged Episodes of Acute Diarrhea Reduce Growth and Increase Risk of Persistent Diarrhea in Children

Prolonged episodes of acute diarrhea (ProD; duration 7-13 days) or persistent diarrhea (PD; duration ≥14 days) are important causes of undernutrition, yet the epidemiology and nutritional impact of ProD are poorly understood. We conducted a 10-year cohort study of 414 children from a Brazilian shantytown who were followed from birth; data were collected on diarrhea, enteric pathogens, and anthropometry. During 1276 child-years of observation, we recorded 3257 diarrheal episodes. ProD was twice as common as PD (12% and 5% of episodes, respectively); ProD and PD together accounted for 50% of all days with diarrhea. ProD was more common in infants whose mothers had not completed primary school (relative risk [RR], 2.1; 95% confidence interval: 1.02-2.78). Early weaning was associated with earlier onset of ProD (Spearman ρ = 0.309; P = .005). Infants with ProD were twice as likely to develop PD in later childhood (log rank, P = .002) compared with infants with only acute diarrhea (AD; duration <7 days), even after controlling for confounders. Children's growth was more severely stunted before their first episode of ProD, compared with AD (mean height-for-age Z score (HAZ) -0.81 vs -0.51, respectively, P < .05, unpaired t test). Following ProD, HAZ (ΔHAZ = -0.232) and weight-for-age (ΔWAZ = -0.26) significantly decreased (P < .005 in paired t tests). ProD was associated with Cryptosporidium and Shigella infections. ProD accounts for significant morbidity and identifies children at risk of a vicious cycle of diarrhea and malnutrition. Further studies are needed to address the recognition and control of ProD and its consequences in resource-limited settings and assess its role in PD pathogenesis.

Development of a mechanism-based high-throughput screen assay for leucine-rich repeat kinase 2—Discovery of LRRK2 inhibitors

LRRK2 is a large and complex protein that possesses kinase and GTPase activities and has emerged as the most relevant player in PD pathogenesis possibly through a toxic gain-of-function mechanism. Kinase activity is a critical component of LRRK2 function and represents a viable target for drug discovery. We now report the development of a mechanism-based TR-FRET assay for the LRRK2 kinase activity using full-length LRRK2. In this assay, PLK-peptide was chosen as the phosphoryl acceptor. A combination of steady-state kinetic studies and computer simulations was used to calculate the initial concentrations of ATP and PLK-peptide to generate a steady-state situation that favors the identification of ATP noncompetitive inhibitors. The assay was also run in the absence of GTP. Under these conditions, the assay was sensitive to inhibitors that directly interact with the kinase domain and those that modulate the kinase activity by directly interacting with other domains including the GTPase domain. The assay was optimized and used to robustly evaluate our compound library in a 384-well format. An inhibitor identified through the screen was further characterized as a noncompetitive inhibitor with both ATP and PLK-peptide and showed similar inhibition against LRRK2 WT and the mutant G2019S.

Pathogenesis of PD: Missing the point

Pathogenesis of PD: Missing the point

The pattern of neuronal loss and survival may reflect differential expression of proteasome activators in Parkinson's disease

The basis of neuronal vulnerability, degeneration, and sparing in PD are unknown, but there is increasing evidence to suggest that the ubiquitin-proteasome system (UPS) plays an important role in the pathogenesis of the disorder. In this study, we employed an immunocytochemical approach to determine if the differential expression of key UPS components in various brain regions and cells might underlie the pattern of neuronal degeneration and survival seen in PD. We showed that the ubiquitin activating enzyme (E1), ubiquitin conjugating enzyme (E2), and 26/20S proteasome alpha- and beta-subunits, are abundantly expressed in the substantia nigra pars compacta (SNc) and in cultured dopaminergic neurons. Although the proteasome activator PA700 is expressed in the medial SNc, levels are low in the lateral region, and expression of the other proteasome activator, PA28, is near absent in the entire SNc. PA28 (but not PA700) was found to be poorly expressed in noradrenergic neurons in the locus coeruleus (LC) compared with adjacent cells in the mesencephalic nucleus. PA700 and PA28 are also poorly expressed in dopaminergic neurons compared with other cell types in culture. Inhibition of proteasomal function, generation of misfolded proteins, induction of oxidative stress or impairment of mitochondrial complex I activity, caused a compensatory upregulation in PA700 and PA28 in a variety of cells but not in dopaminergic neurons in culture. These findings are consistent with the demonstration that, in sporadic PD, proteasomal activity and levels of PA700/PA28 are reduced in the SNc but are markedly upregulated in regions/cells that are spared from the neurodegenerative process. Thus, the differential distribution and activity of proteasome activations could play a significant role in the pathogenesis of PD.

Mesenchymal stem cell transplantation attenuates blood brain barrier damage and neuroinflammation and protects dopaminergic neurons against MPTP toxicity in the substantia nigra in a model of Parkinson's disease

Immunomodulatory effects of transplanted mesenchymal stem cells (MSCs) in the treatment of Parkinson's disease were studied in the MPTP-induced mouse model. MPTP treatment induced a significant loss of dopaminergic neurons, decreased expressions of claudin 1, claudin 5 and occludin in the substantia nigra compacta (SNc), and functional damage of the blood brain barrier (BBB). Our study further discovered that infiltration of MBLs into the brain to bind with microglia was detected in the SNc of MPTP-treated mice, suggesting that the BBB compromise and MBL infiltration might be involved in the pathogenesis of MPTP-induced PD. In addition, MPTP treatment also increased the expression of mannose-binding lectins (MBLs) in the liver tissue. Intravenous transplantation of MSCs into MPTP-treated mice led to recovery of BBB integrity, suppression of MBL infiltration at SNc and MBL expression in the liver, suppression of microglial activation and prevention of dopaminergic neuron death. No transplanted MSCs were observed to differentiate into dopaminergic neurons, while the MSCs migrated into the SNc and released TGF-β1 there. Therefore, intravenous transplantation of MSCs which protect dopaminergic neurons from MPTP toxicity may be engaged in anyone or a combination of these mechanisms: repair of the BBB, reduction of MBL in the brain, inhibition of microglial cytotoxicity, and direct protection of dopaminergic neurons.

Conjugal Parkinsonism and Parkinson disease: A case series with environmental risk factor analysis

PD occurring in married couples, “conjugal PD” represents a unique opportunity to study environmental risk factors for PD due to the shared environment. This retrospective study of non-related married individuals who both presented to the Washington University Movement Disorders Center between 1994 and 2005 investigated the clinical presentation, therapy response, and disease course in conjugal PD subjects. In addition, an occupational, residential, and environmental survey was administered to elucidate potential shared environmental risk factors. Eighteen married subjects had a clinical picture suggestive of idiopathic Parkinson disease. Average age of motor symptom onset was 66.1 (±6.22) years in women, 63.4 (±7.87) years in men. Subjects cohabitated an average of 39.9 years prior to motor symptom onset in the first affected spouse and an average of nine years elapsed prior to symptom onset in their partner. Disease course in conjugal pairs varied substantially. Seventeen out of eighteen subjects reported at least one environmental exposure of interest. Concordant exposures were residential, non-occupational pesticide and heavy metal exposure, each reported by 77.8% (7/9) of couples. Multiple exposures were reported by 88.9% (16/18) of subjects, most often residential agricultural chemical and heavy metal in combination. This case series of conjugal PD suggests that combined residential exposures may be important in the pathogenesis of idiopathic PD. Larger conjugal PD studies may permit stratification of concordant environmental exposures to determine dose responsiveness and relative contributions to PD risk.

Chronic Administration with Rotenone does not Enhance MPTP Neurotoxicity in C57BL/6 Mice

Systematic administration of rotenone as one of pesticides is known to produce degeneration of nigral dopaminergic neurons and motor deficits in experimental animals. Here, we investigated to determine whether systematic administration of rotenone causes the increased susceptibility in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-treated mice. Rotenone was injected into MPTP-treated mice over a period of 4 weeks. Thereafter, we evaluated the effect of rotenone 1, 3, and 6 weeks after the cessation of treatment with rotenone. In the present study with HPLC analysis, rotenone did not enhance MPTP-induced dopaminergic neurotoxicity in mice. Furthermore, MPTP + rotenone (9 mg/kg)-treated mice exhibit a significant loss of motor activity 1 day after the cessation of treatment with rotenone, However, no significant change of motor activity was found in MPTP-treated and MPTP + rotenone (9 mg/kg)-treated animals 6 weeks after the cessation of treatment with 0.5% carboxymethyl cellulose or rotenone. Our Western blot analysis study demonstrated that the change of tyrosine hydroxylase and glial fibrillary acidic protein protein levels in MPTP-treated mice was similar than that in MPTP + rotenone-treated animals. These results suggest that rotenone did not enhance MPTP neurotoxicity in mice. Our findings suggest that rotenone is not a reliable model for PD. Thus, our findings provide further valuable information for the pathogenesis of PD for exposure to agricultural pesticides.

Molecular and Neurochemical Mechanisms in PD Pathogenesis

Oxidation of dopamine to aminochrome seems to be a normal process leading to aminochrome polymerization to form neuromelanin, since normal individuals have this pigment in their dopaminergic neurons in the substantia nigra. The neurons lost in individuals with Parkinson's disease are dopaminergic neurons containing neuromelanin. This raises two questions. First, why are those cells containing neuromelanin lost in this disease? Second, what is the identity of the neurotoxin that induces this cell death? We propose that aminochrome is the agent responsible for the death of dopaminergic neurons containing neuromelanin in individuals with Parkinson's disease. The normal oxidative pathway of dopamine, in which aminochrome polymerizes to form neuromelanin, can be neurotoxic if DT-diaphorase is inhibited under certain conditions. Inhibition of DT-diaphorase allows two neurotoxic reactions to proceed: (i) the formation of aminochrome adducts with alpha-synuclein, which induce and stabilize the formation of neurotoxic protofibrils; and (ii) the one electron reduction of aminochrome to the neurotoxic leukoaminochrome o-semiquinone radical. Therefore, we propose that DT-diaphorase is an important neuroprotective enzyme in dopaminergic neurons containing neuromelanin.

Identification of the amino acid sequence motif of α-synuclein responsible for macrophage activation

α-Synuclein (Syn) is implicated in the pathogenesis of PD and related neurodegenerative disorders. Recent studies have also shown that α-synuclein can activate microglia and enhance dopaminergic neurodegeneration. The mechanisms of microglia activation by α-synuclein, however, are not well understood. In this study, we found that not only α-synuclein but also β- and γ-synucleins activated macrophages (RAW 264.7) in vitro. Macrophages treated with synuclein proteins secreted TNF-α in a dose-dependent manner. Synuclein family proteins also increased mRNA transcription of COX-2 and iNOS. Two α-synuclein deletion mutants, SynΔNAC and Syn61–140, activated macrophages, while deletion mutants Syn1–60 and Syn96–140 did not significantly activate them. Finally, we demonstrated that macrophage activation by α-synuclein was accompanied by phosphorylation of ERK. These results suggest that synuclein family proteins can activate macrophages, and that macrophage activation needs both the N-terminal and C-terminal domains of α-synuclein, but not the central NAC region.

Osteoblast Apoptosis in Periodontal Disease: Role of TNF-Related Apoptosis-Inducing Ligand

Periodontal disease (Pd) is characterized by an increased osteoclast resorption and a decreased osteoblast (OB) bone formation. OBs obtained from alveolar bone of Periodontitis patients (Pp) undergo apoptosis in the presence of TNF-related apoptosis-inducing ligand (TRAIL). We studied the intracellular apoptotic pathway induced by TRAIL; TRAIL death (DR4, DR5) and decoy (DcR1, DcR2) receptors expression in Periodontitis patients OBs (PpOBs), and we measured the concentration of TRAIL in the serum of Pp. We demonstrated that DNA fragmentation and activation of caspase-8 and caspase-3 in PpOBs, following TRAIL stimulation, occurred in shorter time; moreover, a higher amount of both caspases was activated in order to direct OBs. Down-regulation of DcR2 in PpOBs was demonstrated and high TRAIL levels were detected in the serum of Pp. In conclusion, our data suggest that PpOBs are more sensitive to TRAIL-induced apoptosis when compared to the control group. The down-regulation of DcR2 possibly leads to an imbalanced ratio between death and decoy receptors. Our findings highlight a role of TRAIL in the pathogenesis of Pd.

Iron contributes to the formation of catechol isoquinolines and oxidative toxicity induced by overdose dopamine in dopaminergic SH-SY5Y cells

The selective loss of dopaminergic neurons in Parkinson's disease is suspected to correlate with the increase of cellular iron, which may be involved in the pathogenesis of PD by promotion of oxidative stress. This research investigated dopamine-induced oxidative stress toxicity contributed by iron and the production of dopamine-derived neurotoxins in dopaminergic SH-SY5Y cells. After the SH-SY5Y cells were pre-incubated with dopamine and Fe2+ for 24 h, the cell viability, hydroxyl radical, melondialdehyde, cell apoptosis, and catechol isoquinolines were measured by lactate dehydrogenase assay, salicylic acid trapping method, thiobarbuteric acid assay, Hoechst 33258 staining and HPLC-electrochemical detection (HPLC-ECD), respectively. (1) Optimal dopamine (150 micromol/L) and Fe2+ (40 or 80 micromol/L) significantly increased the concentrations of hydroxy radicals and melondialdehyde in SH-SY5Y cells. (2) Induction with dopamine alone or dopamine and Fe2+ (dopamine/Fe2+) caused cell apoptosis. (3) Compared with untreated cells, the catechol isoquinolines, salsolinol and N-methyl-salsolinol in dopamine/Fe2+-induced cells were detected in increasing amounts. Due to dopamine/Fe2+-induced oxidative stress similar to the state in the parkinsonian substantia nigra neurons, dopamine and Fe2+ impaired SH-SY5Y cells could be used as the cell oxidative stress model of Parkinson's disease. The catechol isoquinolines detected in cells may be involved in the pathogenesis of Parkinson's disease as potential neurotoxins.

Can anti-inflammatory agents protect against Parkinson‘s disease?

Beate Ritz†, Angelika D Wahner, Yvette Bordelon & Jeff M Bronstein †Author for correspondence UCLA School of Public Health, Box 951772, 650 Charles E Young Drive, Los Angeles, CA 90095-1772, USA Tel.: +1 310 206 7458; Fax: +1 310 206 6039; britz@ucla.edu ‘...inflammation in brain tissue contributes to the pathogenesis of PD, and anti-inflammatory drugs may be capable of preventing or reducing neuronal degeneration caused by neuroinflammation.’

Multiplex Analysis of Cytokines in the Serum and Cerebrospinal Fluid of Patients With Alzheimer's Disease by Color-Coded Bead Technology

Background and purposeThe availability and promise of effective treatments for neurodegenerative disorders are increasing the importance of early diagnosis. Having molecular and biochemical markers of Alzheimer's disease (AD) would complement clinical approaches, and further the goals of early and accurate diagnosis. Combining multiple biomarkers in evaluations significantly increases the sensitivity and specificity of the biochemical tests.MethodsIn this study, we used color-coded bead-based Luminex technology to test the potential of using chemokines and cytokines as biochemical markers of AD. We measured the levels of 22 chemokines and cytokines in the serum and cerebrospinal fluid (CSF) of 32 de novo patients (13 controls, 11 AD, and 8 Parkinson's disease [PD]).ResultsMCP-1 was the only cytokine detectable in CSF, and its levels did not differ between control and disease groups. However, the serum concentration of eotaxin was significantly higher in AD patients than in the control group.ConclusionsThe analysis of multiple inflammatory mediators revealed marginal differences in their CSF and serum concentrations for the differential diagnosis of AD and PD. These results provide evidence that immunological responses are not major contributors to the pathogenesis of AD and PD.

Pink1 Parkinson mutations, the Cdc37/Hsp90 chaperones and Parkin all influence the maturation or subcellular distribution of Pink1

Mutations in the ubiquitously expressed gene PTEN-induced kinase 1 (Pink1) cause autosomal recessive Parkinson's disease. Pink1 encodes a putative serine/threonine kinase with an N-terminal mitochondrial targeting sequence. The mechanism that leads to selective degeneration of dopaminergic neurons via Pink1 mutations is unknown. A full-length pre-protein (66 kDa) and an N-terminally truncated mature form (55 kDa) have been described in human brain. Here, we report that the endogenous 66 kDa and 55 kDa Pink1 forms in cultured cells are not exclusive to mitochondria but also occur in cytosolic and microsome-rich fractions. Pink1 66 kDa is the predominant isoform in cultured cells. Using unbiased analyses of immunoisolated Pink1 complexes by mass spectrometry, co-immunoprecipitation and Hsp90 inhibitor studies, we identify Pink1 as a novel Cdc37/Hsp90 client kinase. This chaperone system influences both the subcellular distribution and the 66/55 kDa protein ratio of Pink1. PD-causing Pink1 mutations decrease whereas Parkin expression increases the Pink1 66/55 kDa protein ratio, biochemically linking Pink1 and Parkin and highlighting the potential relevance of this ratio for PD pathogenesis. Finally, we document the influence of Parkin on Pink1 subcellular distribution, providing further evidence for a common pathogenic pathway in recessive PD.

Microglial PHOX and Mac‐1 are essential to the enhanced dopaminergic neurodegeneration elicited by A30P and A53T mutant alpha‐synuclein

alpha-Synuclein, a gene whose mutations, duplication, and triplication has been linked to autosomal dominant familial Parkinson's disease (fPD), appears to play a central role in the pathogenesis of sporadic PD (sPD) as well. Enhancement of neurodegeneration induced by mutant alpha-synuclein has been attributed to date largely to faster formation of alpha-synuclein aggregates in neurons. Recently, we reported that microglial activation enhances wild type (WT) alpha-synuclein-elicited dopaminergic neurodegeneration. In the present study, using a primary mesencephalic culture system, we tested whether mutated alpha-synuclein could activate microglia more powerfully than WT alpha-synuclein, thereby contributing to the accelerated neurodegeneration observed in fPD. The results showed that alpha-synuclein with the A30P or A53T mutations caused greater microglial activation than WT alpha-synuclein. Furthermore, the extent of microglial activation paralleled the degree of dopaminergic neurotoxicity induced by WT and mutant alpha-synuclein. Mutant alpha-synuclein also induced greater production of reactive oxygen species than WT alpha-synuclein by NADPH oxidase (PHOX), and PHOX activation was linked to direct activation of macrophage antigen-1 (Mac-1) receptor, rather than alpha-synuclein internalization via scavenger receptors. These results have, for the first time, demonstrated that microglia are also critical in enhanced neurotoxicity induced by mutant alpha-synuclein.

A Genomic Pathway Approach to a Complex Disease: Axon Guidance and Parkinson Disease

While major inroads have been made in identifying the genetic causes of rare Mendelian disorders, little progress has been made in the discovery of common gene variations that predispose to complex diseases. The single gene variants that have been shown to associate reproducibly with complex diseases typically have small effect sizes or attributable risks. However, the joint actions of common gene variants within pathways may play a major role in predisposing to complex diseases (the paradigm of complex genetics). The goal of this study was to determine whether polymorphism in a candidate pathway (axon guidance) predisposed to a complex disease (Parkinson disease [PD]). We mined a whole-genome association dataset and identified single nucleotide polymorphisms (SNPs) that were within axon-guidance pathway genes. We then constructed models of axon-guidance pathway SNPs that predicted three outcomes: PD susceptibility (odds ratio = 90.8, p = 4.64 × 10−38), survival free of PD (hazards ratio = 19.0, p = 5.43 × 10−48), and PD age at onset (R 2 = 0.68, p = 1.68 × 10−51). By contrast, models constructed from thousands of random selections of genomic SNPs predicted the three PD outcomes poorly. Mining of a second whole-genome association dataset and mining of an expression profiling dataset also supported a role for many axon-guidance pathway genes in PD. These findings could have important implications regarding the pathogenesis of PD. This genomic pathway approach may also offer insights into other complex diseases such as Alzheimer disease, diabetes mellitus, nicotine and alcohol dependence, and several cancers.