Parkinsonism and neurological manifestations of influenza throughout the 20th and 21st centuries

Henry, Julia; Smeyne, Richard J.; Jang, Haeman; Miller, B. Lynn; Okun, Michael S.

doi:10.1016/j.parkreldis.2010.06.012

Cited by 96 publications

(91 citation statements)

References 42 publications

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“…Moreover, in regions infected by the H5N1 virus, they observed aSyn aggregation that persisted long after resolution of the infection. This observation provides evidence for the involvement of viral infection and also possibly the immune response in generating aSyn aggregation and, potentially, the pathogenesis of PD (8,10,12). The mechanism by which infections cause aSyn aggregation remains unknown, however.…”

mentioning

confidence: 69%

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Caspase-1 causes truncation and aggregation of the Parkinson’s disease-associated protein α-synuclein

Wang

Nguyen

Burlak

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

215

184

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The aggregation of α-synuclein (aSyn) leading to the formation of Lewy bodies is the defining pathological hallmark of Parkinson's disease (PD). Rare familial PD-associated mutations in aSyn render it aggregation-prone; however, PD patients carrying wild type (WT) aSyn also have aggregated aSyn in Lewy bodies. The mechanisms by which WT aSyn aggregates are unclear. Here, we report that inflammation can play a role in causing the aggregation of WT aSyn. We show that activation of the inflammasome with known stimuli results in the aggregation of aSyn in a neuronal cell model of PD. The insoluble aggregates are enriched with truncated aSyn as found in Lewy bodies of the PD brain. Inhibition of the inflammasome enzyme caspase-1 by chemical inhibition or genetic knockdown with shRNA abated aSyn truncation. In vitro characterization confirmed that caspase-1 directly cleaves aSyn, generating a highly aggregation-prone species. The truncation-induced aggregation of aSyn is toxic to neuronal culture, and inhibition of caspase-1 by shRNA or a specific chemical inhibitor improved the survival of a neuronal PD cell model. This study provides a molecular link for the role of inflammation in aSyn aggregation, and perhaps in the pathogenesis of sporadic PD as well.ver the past two decades, studies stimulated by the discovery of genetic mutations occurring in familial Parkinson's disease (PD) have generated a number of hypotheses concerning potential mechanisms of PD pathogenesis. Nonetheless, the causes and mechanism of sporadic PD, which constitutes the majority of cases, remain unknown.Before the genetic discoveries, epidemiologic evidence suggested environmental toxins, traumatic brain injury, and viral infection as potential causes of idiopathic PD (1-7). All of these insults could cause neural inflammation, a common feature of PD brains; however, whether neural inflammation contributes to the etiology of the disease or is part of its effect remained unclear. Suggestive evidence indicating the involvement of inflammation in the pathogenesis of PD emerged after an outbreak of encephalitis lethargica following the 1918 influenza pandemic, which killed approximately 1 million people and left many survivors with postencephalitic Parkinsonism (PEP). Affected persons presented with cardinal symptoms of typical Parkinson's disease, including stooped posture, masklike faces, muscular rigidity, and tremorous extremities. Contemporary cases of viral infection-associated Parkinsonism are rare, but both epidemiology and patient case studies indicate that infection-associated PD still occurs today (8-10).The role of viral infection in the pathogenesis of PD has been a controversial subject for more than 50 years. Proponents have pointed out the known close temporal association between infection and PEP, whereas opponents have cited studies that failed to find any viral remnants in the brains of affected patients. Moreover, there were no known routes for peripheral viral migration into the central nervous system (CNS). Recently, R. Smey...

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confidence: 69%

“…Affected persons presented with cardinal symptoms of typical Parkinson's disease, including stooped posture, masklike faces, muscular rigidity, and tremorous extremities. Contemporary cases of viral infection-associated Parkinsonism are rare, but both epidemiology and patient case studies indicate that infection-associated PD still occurs today (8)(9)(10).…”

mentioning

confidence: 99%

Caspase-1 causes truncation and aggregation of the Parkinson’s disease-associated protein α-synuclein

Wang

Nguyen

Burlak

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

215

184

View full text Add to dashboard Cite

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“…Epidemiologic studies pointed to an association between early-life viral infections and postencephalitic PD, while case reports tend to relate viral infections to the development of acute Parkinsonism (Duvoisin et al , 1972; Elizan and Casals, 1991; Ghaemi et al , 2000; Henry et al , 2010; Liu et al , 2003). Experimental exposure of neonatal Fisher 344 rats to Japanese encephalitis virus can induce degeneration of nigral dopamine neurons, gliosis in the SN, and movement disorders resembling human PD (Ogata et al, 1997).…”

Section: The Environmental Causes Of Pdmentioning

confidence: 99%

Gene–environment interactions: Key to unraveling the mystery of Parkinson's disease

Gao

Hong

2011

Progress in Neurobiology

146

111

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Parkinson’s disease (PD) is the second most common neurodegenerative disease. The gradual, irreversible loss of dopamine neurons in the substantia nigra isthe signature lesion of PD. Clinical symptoms of PD become apparent when 50–60% of nigral dopamine neurons are lost. PD progresses insidiously for 5–7 years (preclinical period) and then continues to worsen even under the symptomatic treatment. To determine what triggers the disease onset and what drives the chronic, self-propelling neurodegenerative process becomes critical and urgent, since lack of such knowledge impedes the discovery of effective treatments to retard PD progression. At present, available therapeutics only temporarily relieve PD symptoms. While the identification of causative gene defects in familial PD uncovers important genetic influences in this disease, the majority of PD cases are sporadic and idiopathic. The current consensus suggests that PD develops from multiple risk factors including aging, genetic predisposition, and environmental exposure. Here, we briefly review research on the genetic and environmental causes of PD. We also summarize very recent genome-wide association studies on risk gene polymorphisms in the emergence of PD. We highlight the new converging evidence on gene-environment interplay in the development of PD with an emphasis on newly developed multiple-hit PD models involving both genetic lesions and environmental triggers.

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“…In another study, 6 of 25 patients from a Colorado epidemic of WEEV presented with a "parkinsonian syndrome" in the form of severe, progressive neurological sequelae (31). The concept of virus-induced Parkinsonism has been reviewed in the scientific literature (32)(33)(34).…”

Section: Discussionmentioning

confidence: 99%

Entry Sites of Venezuelan and Western Equine Encephalitis Viruses in the Mouse Central Nervous System following Peripheral Infection

Phillips

Rico

Stauft

et al. 2016

J Virol

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Venezuelan and western equine encephalitis viruses (VEEV and WEEV; Alphavirus; Togaviridae) are mosquito-borne pathogens causing central nervous system (CNS) disease in humans and equids. Adult CD-1 mice also develop CNS disease after infection with VEEV and WEEV. Adult CD-1 mice infected by the intranasal (i.n.) route, showed that VEEV and WEEV enter the brain through olfactory sensory neurons (OSNs). In this study, we injected the mouse footpad with recombinant WEEV (McMillan) or VEEV (subtype IC strain 3908) expressing firefly luciferase (fLUC) to simulate mosquito infection and examined alphavirus entry in the CNS. Luciferase expression served as a marker of infection detected as bioluminescence (BLM) by in vivo and ex vivo imaging. BLM imaging detected WEEV and VEEV at 12 h postinoculation (hpi) at the injection site (footpad) and as early as 72 hpi in the brain. BLM from WEEV.McM-fLUC and VEEV.3908-fLUC injections was initially detected in the brain's circumventricular organs (CVOs). No BLM activity was detected in the olfactory neuroepithelium or OSNs. Mice were also injected in the footpad with WEEV.McM expressing DsRed (Discosoma sp.) and imaged by confocal fluorescence microscopy. DsRed imaging supported our BLM findings by detecting WEEV in the CVOs prior to spreading along the neuronal axis to other brain regions. Taken together, these findings support our hypothesis that peripherally injected alphaviruses enter the CNS by hematogenous seeding of the CVOs followed by centripetal spread along the neuronal axis. IMPORTANCEVEEV and WEEV are mosquito-borne viruses causing sporadic epidemics in the Americas. Both viruses are associated with CNS disease in horses, humans, and mouse infection models. In this study, we injected VEEV or WEEV, engineered to express bioluminescent or fluorescent reporters (fLUC and DsRed, respectively), into the footpads of outbred CD-1 mice to simulate transmission by a mosquito. Reporter expression serves as detectable bioluminescent and fluorescent markers of VEEV and WEEV replication and infection. Bioluminescence imaging, histological examination, and confocal fluorescence microscopy were used to identify early entry sites of these alphaviruses in the CNS. We observed that specific areas of the brain (circumventricular organs [CVOs]) consistently showed the earliest signs of infection with VEEV and WEEV. Histological examination supported VEEV and WEEV entering the brain of mice at specific sites where the blood-brain barrier is naturally absent. E astern, Venezuelan, and western equine encephalitis viruses (EEEV, VEEV, and WEEV; Alphavirus; Togaviridae) are mosquito-borne viruses in the Americas causing central nervous system (CNS) disease in humans and equids (1). EEEV, VEEV, and WEEV are maintained in nature via transmission cycles between vertebrate hosts and specific mosquito species (2). Historically, these alphaviruses have caused sporadic epizootics and epidemics in horses and humans, respectively (1, 3). Outbreaks have led to significant rates of morbidity...

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Parkinsonism and neurological manifestations of influenza throughout the 20th and 21st centuries

Cited by 96 publications

References 42 publications

Caspase-1 causes truncation and aggregation of the Parkinson’s disease-associated protein α-synuclein

Caspase-1 causes truncation and aggregation of the Parkinson’s disease-associated protein α-synuclein

Gene–environment interactions: Key to unraveling the mystery of Parkinson's disease

Entry Sites of Venezuelan and Western Equine Encephalitis Viruses in the Mouse Central Nervous System following Peripheral Infection

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