Post-encephalitic Parkinsonism: current experience

Rail, David; Scholtz, Carl L.; Swash, Michael

doi:10.1136/jnnp.44.8.670

Cited by 109 publications

(52 citation statements)

References 15 publications

(12 reference statements)

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“…Our results provide a direct association of caspase-1 truncation of aSyn with aggregation and neuronal cell toxicity, and hence suggest that inflammation may play an important role in the pathogenesis of PD, as numerous reports have suggested (8,9,52,53), as well as other neurologic diseases (53)(54)(55)(56). Our data suggest that modulation of caspase-1 activity (or inflammasome activity) might be an effective strategy for preventing or treating PD.…”

Section: Discussionsupporting

confidence: 65%

See 1 more Smart Citation

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.

217

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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Section: Discussionsupporting

confidence: 65%

“…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.

217

184

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“…Associations were first established towards the end of the first world war when the H1N1 influenza-A pandemic was coupled with a dramatic increase in post-encephalitic Parkinsonism (PEP) (also referred to as "sleeping sickness" or von Economo encephalitis) (Jang et al, 2009a;Rail et al, 1981;Tansey et al, 2007). People born during this time were at a 2-3 fold increased risk of developing PD, with PEP implicated in 50% of all Parkinsonism cases (Jang et al, 2009a;Tansey et al, 2007).…”

Section: Epidemiological Evidencementioning

confidence: 99%

Contributions of central and systemic inflammation to the pathophysiology of Parkinson's disease

Collins¹,

Toulouse²,

Connor³

et al. 2012

Neuropharmacology

253

153

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“…Toxins that can trigger an acute parkinsonian state include 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine, organophosphate pesticides, carbon monoxide, and methanol [3]. Parkinsonism may also follow viral infections, for example von Economo's encephalitis [4], Japanese B encephalitis [5], Coxsackie B2 infection, West Nile infection, or human immunodeficiency virus infection. Chemotherapeutic agents or treatments for central nervous system malignancy may also trigger acute parkinsonism, either by causing direct injury to the basal ganglia (irradiation for bone marrow transplant [6]) or selective nigral toxicity (cytosine arabinoside [7], paclitaxel [8]).…”

Section: Acute Parkinsonismmentioning

confidence: 99%

Treatment of Movement Disorder Emergencies

Frucht

2014

Neurotherapeutics

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Movement disorder emergencies are defined as clinical scenarios where a movement disorder develops over hours to days, and in which morbidity and even mortality can result from failure to appropriately diagnose and manage the patient. The last decade has seen increasing recognition of various movement disorder emergencies, including acute parkinsonism, neuroleptic malignant syndrome, respiratory compromise in multiple system atrophy, dystonic storm, oculogyric crisis, and hemiballism, among others. This article will review the major movement disorder emergencies encountered in the hospital and office, emphasizing practical management and treatment.

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Post-encephalitic Parkinsonism: current experience

Cited by 109 publications

References 15 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

Contributions of central and systemic inflammation to the pathophysiology of Parkinson's disease

Treatment of Movement Disorder Emergencies

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