Parkinson's disease

Clustering of Parkinson disease: shared cause or coincidence?

Kumar A, Calne SM, Schulzer M, Mak E, Wszolek Z, Van Netten C, Tsui JK, Stoessl AJ, Calne DB. Pacific Parkinson's Research Centre, Vancouver Hospital and Health Sciences Centre, University of British Columbia, 2221 Wesbrook Mall, Vancouver, BC, Canada V6T 2B5. BACKGROUND: The spatial and temporal pattern of excessive disease occurrence, termed clustering, may provide clues about the underlying etiology. OBJECTIVE: To report the occurrence of 3 clusters of Parkinson disease (PD) in Canada. DESIGN AND PATIENTS: We determined the population groups containing the clusters, geographical limits, and duration of exposure to the specific environments. We tested whether there was an excessive presence of Parkinson disease by calculating the probability of the observed cases occurring under the null hypothesis that the disease developed independently and at random in cluster subjects. Results of genetic testing for mutations in the alpha-synuclein, parkin, tau genes, and spinocerebellar ataxia genes (SCA2 and SCA3) were negative. RESULTS: The probabilities of random occurrence (P values) in the 3 clusters were P = 7.9 x 10 (-7)for cluster 1, P = 2.6 x 10 (-7)for cluster 2, and P = 1.5 x 10 (-7)for cluster 3. CONCLUSIONS: Our findings indicate an important role for environmental causation in Parkinson disease. A possible role exists for environmental factors such as viral infection and toxins in the light of current evidence.

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Nature Reviews Neuroscience 10, 393 (June 2009) | doi:10.1038/nrn2650

Neurodegenerative disease: NURR1 puts a dampener on inflammationThe complex biological response of vascular tissues to harmful stimuli such as pathogens or damaged cells. It is a protective attempt by the organism to remove the injurious stimuli as well as initiate the healing process for the tissue.

Katherine Whalley

The nuclear receptorIntracellular receptor proteins that bind to hydrophobic signal molecules (such as steroid and thyroid hormones) or intracellular metabolites and are thus activated to bind to specific DNA sequences which affects transcription. NURR1 (also known as NR4A2) has an essential role in the development and maintenance of dopaminergic neurons, and mutations in this protein cause a familial form of Parkinson's disease (PD). Now, a study from Saijo et al. suggests a previously unknown function of NURR1 in microglia and astrocytes in protecting dopaminergic neurons from inflammation-induced death.

Growing evidence suggests that inflammatory processes contribute to neuropathology in PD. For example, experimentally infusing inflammatory substances such as lipopolysaccharide (LPS) into the brain can replicate some of the pathology of PD. In macrophages, NURR1 expression can be induced by LPS, prompting the authors to investigate the influence of NURR1 on the effects of LPS in the CNS. They found that injecting lentiviruses encoding short hairpin RNAs against NURR1 (shNURR1) into the substantia nigra of mice significantly accelerated and augmented the loss of dopaminergic neurons in this region in response to LPS, suggesting that NURR1 can protect neurons from LPS-induced cell death.

Next the authors investigated the mechanisms and cell types involved in NURR1's protective effects. Expressing shNURR1 in cultured microglia or astrocytes increased their production of inflammatory mediators, such as tumour necrosis factor- and inducible nitric oxide synthase, in response to LPS. The conditioned media taken from shNURR1 microglia cultures was highly toxic to cultured dopaminergic neurons. Moreover, when the media was sequentially used to culture shNURR1-treated microglia and then shNURR1-treated astrocytes, its toxicity for dopaminergic neurons was increased further, indicating that NURR1 inhibits the production of toxic inflammatory factors in both microglia and astrocytes.

In subsequent experiments, the authors dissected the mechanism by which NURR1 influences the expression of inflammatory genes in astrocytes and microglia. They revealed that NURR1 represses the transcription of these genes by interacting with the transcription factor complex nuclear factor-B–p65 on the gene promoter, a process known as transrepression. This interaction was shown to rely on both the sumoylation of NURR1 and the phosphorylation of p65 by glycogen synthase kinase 3. Furthermore, the authors showed that the co-repressor COREST, together with the chromatin-modifying enzymes that it recruits (histone methyltransferase G9a, lysine-specific demethylase and histone deacetylase 1), is required for NURR1-mediated transrepression. The interaction between NURR1 and COREST required the activity of Nemo-like kinase.

This study describes a previously unknown role for NURR1 in suppressing potentially neurotoxic inflammatory gene expression in microglia and astrocytes and suggests that the loss of this ability might contribute to some forms of PD. The transrepression pathway uncovered may provide further clues to the cause of PD pathology as well as potential therapeutic targets.

Helicobacter. 2005 Aug;10(4):276-87. Role of chronic infection and inflammation in the gastrointestinal tract in the etiology and pathogenesis of idiopathic parkinsonism. Part 2: response of facets of clinical idiopathic parkinsonism to Helicobacter pylori eradication. A randomized, double-blind, placebo-controlled efficacy study. Bjarnason IT, Charlett A, Dobbs RJ, Dobbs SM, Ibrahim MA, Kerwin RW, Mahler RF, Oxlade NL, Peterson DW, Plant JM, Price AB, Weller C.

Section of Neuropharmacology, Institute of Psychiatry, London, UK. Erratum in:

Helicobacter. 2005 Oct;10(5):557. Bjarnason, Inguar T [corrected to Bjarnason, Ingvar T]. Abstract BACKGROUND: Links between etiology/pathogenesis of neuropsychiatric disease and infection are increasingly recognized. AIM: Proof-of-principle that infection contributes to idiopathic parkinsonism. METHODS: Randomized, double-blind, placebo-controlled efficacy study of proven Helicobacter pylori eradication on the time course of facets of parkinsonism. Intervention was 1 week's triple eradication therapy/placebos. Routine deblinding at 1 year (those still infected received open-active), with follow-up to 5 years post-eradication. Primary outcome was mean stride length at free-walking speed, sample size 56 for a difference, active vs. placebo, of 3/4 (between-subject standard deviation). Recruitment of subjects with idiopathic parkinsonism and H. pylori infection was stopped at 31, because of marked deterioration with eradication failure. Interim analysis was made in the 20 who had reached deblinding, seven of whom were receiving antiparkinsonian medication (long-t(1/2), evenly spaced) which remained unchanged. RESULTS: Improvement in stride-length, on active (n = 9) vs. placebo (11), exceeded size of effect on which the sample size was calculated when analyzed on intention-to-treat basis (p = .02), and on protocol analysis of six weekly assessments, including (p = .02) and excluding (p = .05) those on antiparkinsonian medication. Active eradication (blind or open) failed in 4/20, in whom B-lymphocyte count was lower. Their mean time course was: for stride-length, -243 (95% CI -427, -60) vs. 45 (-10, 100) mm/year in the remainder (p = .001); for the ratio, torque to extend to flex relaxed arm, 349 (146, 718) vs. 58 (27, 96)%/ year (p < .001); and for independently rated, visual-analog scale of stance-walk videos (worst-best per individual identical with 0-100 mm), -64 vs. -3 mm from anterior and -50 vs. 11 lateral (p = .004 and .02). CONCLUSIONS: Interim analysis points to a direct or surrogate (not necessarily unique) role of a particular infection in the pathogenesis of parkinsonism. With eradication failure, bolus release of antigen from killed bacteria could aggravate an effect of ongoing infection.

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