Critical Role of Truncated α‐Synuclein and Aggregates in Parkinson's Disease and Incidental Lewy Body Disease

Prasad, Kavita; Beach, Thomas G.; Hedreen, John C.; Richfield, Eric K.

doi:10.1111/j.1750-3639.2012.00597.x

Cited by 57 publications

(82 citation statements)

References 57 publications

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“…Treatment of microglia with tAS leads to a significant increase of ROS production and release of IL-6, CXCL1, and TNF-α. Our results suggest that tAS which was reported previously as a component of Lewy bodies and glial cytoplasmic inclusions (Baba et al,1998; Gai et al,1999; Prasad et al,2012) may play an important pathogenic role to accelerate neuroinflammation and oxidative stress in ASP. Microglia treated with sAS and fAS also present an augmented ROS production and phagocytic activity.…”

Section: Discussionsupporting

confidence: 70%

Toll‐like receptor 4 is required for α‐synuclein dependent activation of microglia and astroglia

Fellner

Irschick

Schanda

et al. 2012

Glia

598

551

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Alpha-synucleinopathies (ASP) are neurodegenerative disorders, characterized by accumulation of misfolded α-synuclein, selective neuronal loss, and extensive gliosis. It is accepted that microgliosis and astrogliosis contribute to the disease progression in ASP. Toll-like receptors (TLRs) are expressed on cells of the innate immune system, including glia, and TLR4 dysregulation may play a role in ASP pathogenesis. In this study we aimed to define the involvement of TLR4 in microglial and astroglial activation induced by different forms of α-synuclein (full length soluble, fibrillized, and C-terminally truncated). Purified primary wild type (TLR4+/+) and TLR4 deficient (TLR4−/−) murine microglial and astroglial cell cultures were treated with recombinant α-synuclein and phagocytic activity, NFκB nuclear translocation, cytokine release, and reactive oxygen species (ROS) production were measured. We show that TLR4 mediates α-synuclein-induced microglial phagocytic activity, pro-inflammatory cytokine release, and ROS production. TLR4−/− astroglia present a suppressed pro-inflammatory response and decreased ROS production triggered by α-synuclein treatment. However, the uptake of α-synuclein by primary astroglia is not dependent on TLR4 expression. Our results indicate the C-terminally truncated form as the most potent inductor of TLR4-dependent glial activation. The current findings suggest that TLR4 plays a modulatory role on glial pro-inflammatory responses and ROS production triggered by α-synuclein. In contrast to microglia, the uptake of alpha-synuclein by astroglia is not dependent on TLR4. Our data provide novel insights into the mechanisms of α-synuclein-induced microglial and astroglial activation which may have an impact on understanding the pathogenesis of ASP. © 2012 Wiley Periodicals, Inc.

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Section: Discussionsupporting

confidence: 70%

Toll‐like receptor 4 is required for α‐synuclein dependent activation of microglia and astroglia

Fellner

Irschick

Schanda

et al. 2012

Glia

598

551

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“…To exclude the possibility that the variations in the synapsin-III levels observed in primary neurons were due to non-dopaminergic neurons or glial cells present in the primary cell cultures, we evaluated the expression of synapsin III in a more uniform dopaminergic cell population -dopaminergic differentiated SH-SY5Y neuroblastoma cells (Bellucci et al, 2008) To confirm whether α-syn affected DAT and synapsin III distribution, besides their expression, we used a differentiated neuronal SK-N-SH cell line that stably expressed a green fluorescent protein (GFP)-conjugated form of DAT to overexpress the SYN120 mutant protein (Bellucci et al, 2011a). This form of α-syn can be found in LBs (Prasad et al, 2012), and promotes α-syn aggregation (Crowther et al, 1998), DAT redistribution (Bellucci et al, 2011a) and the induction of axonal and synaptic damage (Games et al, 2013;GarciaReitbock et al, 2010). We found that SYN120-expressing cells showed intracellular α-syn-and synapsin-III-immunopositive inclusions that contained DAT-GFP, whereas, in control SK-N- SH DAT-GFP cells, both synapsin III and DAT localized predominantly at the plasma membrane (supplementary material Fig.…”

Section: Resultsmentioning

confidence: 99%

α-synuclein and synapsin III cooperatively regulate synaptic function in dopamine neurons

Zaltieri

Grigoletto

Longhena

et al. 2015

Journal of Cell Science

108

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The main neuropathological features of Parkinson's disease are dopaminergic nigrostriatal neuron degeneration, and intraneuronal and intraneuritic proteinaceous inclusions named Lewy bodies and Lewy neurites, respectively, which mainly contain α-synuclein (α-syn, also known as SNCA). The neuronal phosphoprotein synapsin III (also known as SYN3), is a pivotal regulator of dopamine neuron synaptic function. Here, we show that α-syn interacts with and modulates synapsin III. The absence of α-syn causes a selective increase and redistribution of synapsin III, and changes the organization of synaptic vesicle pools in dopamine neurons. In α-syn-null mice, the alterations of synapsin III induce an increased locomotor response to the stimulation of synapsin-dependent dopamine overflow, despite this, these mice show decreased basal and depolarization-dependent striatal dopamine release. Of note, synapsin III seems to be involved in α-syn aggregation, which also coaxes its increase and redistribution. Furthermore, synapsin III accumulates in the caudate and putamen of individuals with Parkinson's disease. These findings support a reciprocal modulatory interaction of α-syn and synapsin III in the regulation of dopamine neuron synaptic function.

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“…Various engineered recombinant truncated forms of aSyn aggregate readily in vitro and form toxic inclusions when overexpressed in animal models (14)(15)(16)(17). Furthermore, C-terminally truncated aSyn is ubiquitously present in Lewy bodies of PD brains, and the amount of truncated forms is correlated with the number and size of Lewy bodies (18,19), suggesting that truncation of aSyn might be an early event that renders it more prone to aggregate into disease-associated conformations. A number of in vitro studies have investigated this possibility and have implicated different proteases that theoretically could truncate aSyn, including neurosin (20), 20S proteasome (21,22), calpain-1 (23), matrix metallo-proteases (MMPs) (24), and cathepsin D (25).…”

Section: Significancementioning

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.

224

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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Critical Role of Truncated α‐Synuclein and Aggregates in Parkinson's Disease and Incidental Lewy Body Disease

Cited by 57 publications

References 57 publications

Toll‐like receptor 4 is required for α‐synuclein dependent activation of microglia and astroglia

Toll‐like receptor 4 is required for α‐synuclein dependent activation of microglia and astroglia

α-synuclein and synapsin III cooperatively regulate synaptic function in dopamine neurons

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

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