Parkinson's disease: the dual hit theory revisited

Neuroscience Centre, Institute of Cell and Molecular Science, Barts and The London School of Medicine and Dentistry, London, United Kingdom.
Annals of the New York Academy of Sciences (Impact Factor: 4.38). 08/2009; 1170(1):615-22. DOI: 10.1111/j.1749-6632.2009.04365.x
Source: PubMed


Accumulating evidence suggests that sporadic Parkinson's disease (sPD) has a long prodromal period during which several nonmotor features develop; in particular, impairment of olfaction, vagal dysfunction, and sleep disorder. Early sites of Lewy pathology are the olfactory bulb and enteric plexuses of the foregut. We propose that a neurotropic pathogen, probably viral, enters the brain via two routes: (a) nasal, with anterograde progression into the temporal lobe; and (b) gastric, secondary to swallowing of nasal secretions in saliva. These secretions might contain a neurotropic pathogen that, after penetration of the epithelial lining, could enter axons of the Meissner's plexus and via transsynaptic transmission reach the preganglionic parasympathetic motor neurons of the vagus nerve. This would allow retrograde transport into the medulla and from here into the pons and midbrain until the substantia nigra is reached and typical aspects of disease commence. Evidence for this theory from the perspective of olfactory and autonomic dysfunction is reviewed and the possible routes of pathogenic invasion are considered. It is concluded that the most parsimonious explanation for the initial events of sPD is pathogenic access to the brain through the foregut and nose-hence the term "dual hit."

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Available from: Kelly Del Tredici, Mar 11, 2015
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    • "Recently, a so-called " dual hit " hypothesis has been proposed for Parkinson's disease (PD); this theory postulates a simultaneous involvement of the olfactory system and the DMNV, following aerosolic exposure to an unidentified pathogen which spreads to the ENS after swallowing [10]. Intriguingly, the dual hit hypothesis seems to fit well with a more general theory that could include prions. "
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    ABSTRACT: Sporadic Creutzfeldt-Jakob disease (sCJD), the most frequent human prion disorder, is characterized by remarkable phenotypic variability, which is influenced by the conformation of the pathologic prion protein and the methionine/valine polymorphic codon 129 of the prion protein gene. While the etiology of sCJD remains unknown, it has been hypothesized that environmental exposure to prions might occur through conjunctival/mucosal contact, oral ingestion, inhalation, or simultaneous involvement of the olfactory and enteric systems. We studied 21 subjects with definite sCJD to assess neuropathological involvement of the dorsal motor nucleus of the vagus and other medullary nuclei and to evaluate possible associations with codon 129 genotype and prion protein conformation.The present data show that prion protein deposition was detected inmedullary nuclei of distinct sCJD subtypes, either valine homozygous or heterozygous at codon 129. These findings suggest that an “environmental exposure” might occur, supporting the hypothesis that external sources of contamination could contribute to sCJD in susceptible hosts. Furthermore, these novel data could shed the light on possible causes of sCJD through a “triple match” hypothesis that identify environmental exposure, host genotype, and direct exposure of specific anatomical regions as possible pathogenetic factors.
    BioMed Research International 06/2015; 2015(396791):9. · 2.71 Impact Factor
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    • "Parkinson's disease (PD) is a progressive neurological disorder characterized by motor behavior dysfunctions such as tremor, muscle rigidity, postural instability and bradykinesia. Although people affected by PD are subjected to a significant preclinical period of 5–6 years (Schapira and Obeso, 2006; Hawkes et al., 2009; Savica et al., 2010), there are numerous non-motor manifestations including autonomic dysfunction, sensory problems, sleep disorders and neuropsychiatric symptoms that precede the onset of motor disabilities by 20 years or more (Poewe, 2006; Reichmann, 2010). In particular, delayed gastric emptying, bloating from small bowel coordination, constipation and defecatory dysfunction are common occurrences in PD and are predicted to predate motor symptoms by at least a decade (Abbott et al., 2001; Savica et al., 2009). "
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    ABSTRACT: Lewy pathology affects the gastrointestinal tract in Parkinson's disease (PD) and recent reports suggest a link between the disorder and gut inflammation. In this study, we investigated enteric neuroprotection and macrophage immunomodulation by 17β-estradiol (E2) and the G protein-coupled estrogen receptor 1 (GPER1) in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) mouse PD model. We found that both E2 and the GPER1 agonist G1 are protective against the loss of dopamine myenteric neurons and inhibited enteric macrophage infiltration in MPTP-treated mice. Coadministration of GPER1 antagonist G15, while completely blocking the neuroprotective and anti-inflammatory effects of G1 also partially prevented those of E2. Interestingly, we found that E2 and G1 treatments could directly alter MPTP-mediated immune responses independently from neurodegenerative processes. Analyses of monocyte/macrophage NF-κB and iNOS activation and FACs immunophenotype indicated that 1-methyl-4-phenylpyridinium (MPP(+)) treatment induces a strong immune response in monocytes, comparable to that of canonical challenge by lipopolysaccharide. In these cells, G1 and E2 treatment are equally potent in promoting a shift toward an anti-inflammatory ''M2" immunophenotype reducing MPP(+)-induced NF-κB and iNOS activation. Moreover, G15 also antagonized the immunomodulatory effects of G1 in MPP(+)-treated macrophages. Together these data provide the first evidence for the role of GPER1 in enteric immunomodulation and neuroprotection. Considering increasing recognition for myenteric pathology as an early biomarker for PD, these findings provide a valuable contribution for better understanding and targeting of future therapeutic strategies. Copyright © 2015. Published by Elsevier Inc.
    Neurobiology of Disease 06/2015; 82. DOI:10.1016/j.nbd.2015.05.017 · 5.08 Impact Factor
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    • "Even slight overexpression or slower degradation of the protein could constitute a risk factor for PD (Ibanez et al. 2004). Whereas the etiology of PD is still unknown and is probably the result of a combination of genetic and environmental factors (Di Monte et al. 2002), Braak and colleagues had postulated the hypothesis that a putative, but still unidentified , environmental pathogen entering by olfactory and/or digestive route could induce αS misfolding and aggregation in specific cell types and reach the brain via a consecutive series of projection neurons (Braak et al. 2006; Hawkes et al. 2009). Searches for environmental factors that might Abstract The etiology of most human neurodegenerative disorders is believed to be multifactorial and consists of an interaction between environmental factors and genetic predisposition. "
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    ABSTRACT: The etiology of most human neurodegenerative disorders is believed to be multifactorial and consists of an interaction between environmental factors and genetic predisposition. Regarding Parkinson's disease (PD), the second most frequent neurodegenerative disease characterized by the aggregation of the alpha-synuclein (αS) protein, numerous epidemiological and experimental studies suggested a possible role of exposure to some pesticides. Whereas epidemiological studies largely failed to identify pesticides specifically involved in PD, it is of critical importance to set up in vitro toxicity studies of pesticides. We measured changes of αS levels following pesticide exposures of human cell lines in vitro, using either ELISA detection of endogenous αS or flow cytometry after overexpression using recombinant adenoviruses. We showed that three pesticides (paraquat, rotenone and maneb), which have frequently been associated with PD, produced a dose-dependent increase in cellular αS levels, but also of αS released into the culture medium. Examining an additional series of 20 pesticides from different families and chemical structures, we found that beside some insecticides, including an organophosphate and three pyrethroids, a majority of the 12 studied fungicides were also producing an αS accumulation, three of them (thiophanate-methyl, fenhexamid and cyprodinil) having similar or more pronounced effects than paraquat. A variety of pesticides can disrupt αS homeostasis in vitro; our data illustrate an experimental strategy that could help in the identification of chemicals that could be specifically involved in PD etiology.
    Archive für Toxikologie 10/2014; DOI:10.1007/s00204-014-1388-2 · 5.98 Impact Factor
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