Cerebrospinal Fluid Cytokines and Neurodegeneration‐Associated Proteins in Parkinson's Disease

Wijeyekoon, Ruwani; Moore, Sarah F.; Farrell, Krista; Breen, David P.; Barker, Roger A.; Williams‐Gray, Caroline H.

doi:10.1002/mds.28015

Cited by 36 publications

(30 citation statements)

References 18 publications

(23 reference statements)

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“…PD often presents with an AD pathology such as senile plaques and neurofibrillary tangles (Apaydin et al, 2002), and several experimental studies have explained the co-pathology of AD and PD. α-synuclein has been shown to co-aggregate with amyloid-β 1-42 (Ono et al, 2012) and tau (Guo et al, 2013), and some of the studies in this review showed that CSF αsynuclein levels were correlated with those of amyloid-β 1-42 (Buddhala et al, 2015;Compta et al, 2015;Skogseth et al, 2015;Hall et al, 2016;Murakami et al, 2019;Wijeyekoon et al, 2020) and tau (Kang et al, 2013;Buddhala et al, 2015;Compta et al, 2015;Hall et al, 2015Hall et al, , 2016Skogseth et al, 2015;Murakami et al, 2019). These reports support an interaction of α-synuclein with amyloid beta and tau in the progressive course of PD and cognitive deterioration.…”

Section: Involvement Of Pathogenic Proteins Other Than α-Synucleinsupporting

confidence: 65%

“…In this cohort, CSF levels of α-synuclein correlated with those of amyloid-β 1-42 and total tau. Wijeyekoon et al (2020) showed that the CSF α-synuclein level was negatively correlated negatively with semantic fluency score and positively with the CSF level of amyloid-β 1-42 in PD.…”

Section: Results Showing That a Higher Csf α-Synuclein Level Indicates Worse Posterior Cognitive Functionmentioning

confidence: 97%

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Mini Review: Correlations of Cognitive Domains With Cerebrospinal Fluid α-Synuclein Levels in Patients With Parkinson's Disease

Murakami

Ono

Shiraishi

et al. 2021

Front. Aging Neurosci.

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The level of α-synuclein, a component of Lewy bodies, in cerebrospinal fluid (CSF) in Parkinson's disease (PD) has attracted recent attention. Most meta-analyses conclude that CSF levels of α-synuclein are decreased in PD. Patients with PD present with cognitive impairment, including frontal/executive dysfunction in the early phase and later emergence of visuospatial and mnemonic deficits. To examine whether CSF α-synuclein levels reflect the activities of various cognitive domains, we reviewed reports examining the association of these levels with cognitive performance in each domain in PD. Among 13 cross-sectional studies, five showed that a lower CSF α-synuclein level was associated with worse cognitive function. In four of these five reports, frontal/executive function showed this association, suggesting a link of the pathophysiology with Lewy bodies. In three other reports, a higher CSF α-synuclein level was associated with temporal-parieto-occipital cognitive deterioration such as memory. In the other five reports, the CSF α-synuclein level did not correlate with cognitive performance for any domain. In four longitudinal studies, a higher baseline CSF α-synuclein level was associated with a worse cognitive outcome, including cognitive processing speed, visuospatial function and memory in two, but not with any cognitive outcome in the other two. The different associations may reflect the heterogeneous pathophysiology in PD, including different pathogenic proteins, neurotransmitters. Thus, more studies of the association between cognitive domains and CSF levels of pathogenic proteins are warranted.

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Section: Involvement Of Pathogenic Proteins Other Than α-Synucleinsupporting

confidence: 65%

Section: Results Showing That a Higher Csf α-Synuclein Level Indicates Worse Posterior Cognitive Functionmentioning

confidence: 97%

Mini Review: Correlations of Cognitive Domains With Cerebrospinal Fluid α-Synuclein Levels in Patients With Parkinson's Disease

Murakami

Ono

Shiraishi

et al. 2021

Front. Aging Neurosci.

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“…PD originates from the progressive loss of nigral dopaminergic (DAergic) neurons, which is accompanied by the accumulation of misfolded aggregated αSyn (αSyn agg ) within Lewy bodies and Lewy neurites which is a classical pathological hallmark of this disease (Dickson, 2012). Additionally, microglia-derived expression of pro-inflammatory cytokines such as IL-1β and TNF-α and the pro-oxidant NOS have been identified in the substantia nigra (SN), putamen, serum, and CSF of PD patients (Knott et al, 2000;Nagatsu et al, 2000;Frigerio et al, 2005;Teschke et al, 2014;Qin et al, 2016;Chen et al, 2018;Wijeyekoon et al, 2020). Numerous mechanisms have been implicated in PD pathogenesis, including mitochondrial dysfunction, endoplasmic reticulum stress (ERS), impaired proteostasis, and chronic neuroinflammation (Block et al, 2007) yet the exact mechanisms underlying increased vulnerability of nigral DAergic neurons to PD pathogenesis remains undefined.…”

Section: Introductionmentioning

confidence: 99%

PKC Delta Activation Promotes Endoplasmic Reticulum Stress (ERS) and NLR Family Pyrin Domain-Containing 3 (NLRP3) Inflammasome Activation Subsequent to Asynuclein-Induced Microglial Activation: Involvement of Thioredoxin-Interacting Protein (TXNIP)/Thioredoxin (Trx) Redoxisome Pathway

Samidurai

Palanisamy

Bargues-Carot

et al. 2021

Front. Aging Neurosci.

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A classical hallmark of Parkinson’s disease (PD) pathogenesis is the accumulation of misfolded alpha-synuclein (αSyn) within Lewy bodies and Lewy neurites, although its role in microglial dysfunction and resultant dopaminergic (DAergic) neurotoxicity is still elusive. Previously, we identified that protein kinase C delta (PKCδ) is activated in post mortem PD brains and experimental Parkinsonism and that it participates in reactive microgliosis; however, the relationship between PKCδ activation, endoplasmic reticulum stress (ERS) and the reactive microglial activation state in the context of α-synucleinopathy is largely unknown. Herein, we show that oxidative stress, mitochondrial dysfunction, NLR family pyrin domain containing 3 (NLRP3) inflammasome activation, and PKCδ activation increased concomitantly with ERS markers, including the activating transcription factor 4 (ATF-4), serine/threonine-protein kinase/endoribonuclease inositol-requiring enzyme 1α (p-IRE1α), p-eukaryotic initiation factor 2 (eIF2α) as well as increased generation of neurotoxic cytokines, including IL-1β in aggregated αSynagg-stimulated primary microglia. Importantly, in mouse primary microglia-treated with αSynagg we observed increased expression of Thioredoxin-interacting protein (TXNIP), an endogenous inhibitor of the thioredoxin (Trx) pathway, a major antioxidant protein system. Additionally, αSynagg promoted interaction between NLRP3 and TXNIP in these cells. In vitro knockdown of PKCδ using siRNA reduced ERS and led to reduced expression of TXNIP and the NLRP3 activation response in αSynagg-stimulated mouse microglial cells (MMCs). Additionally, attenuation of mitochondrial reactive oxygen species (mitoROS) via mito-apocynin and amelioration of ERS via the eIF2α inhibitor salubrinal (SAL) reduced the induction of the ERS/TXNIP/NLRP3 signaling axis, suggesting that mitochondrial dysfunction and ERS may act in concert to promote the αSynagg-induced microglial activation response. Likewise, knockdown of TXNIP by siRNA attenuated the αSynagg-induced NLRP3 inflammasome activation response. Finally, unilateral injection of αSyn preformed fibrils (αSynPFF) into the striatum of wild-type mice induced a significant increase in the expression of nigral p-PKCδ, ERS markers, and upregulation of the TXNIP/NLRP3 inflammasome signaling axis prior to delayed loss of TH+ neurons. Together, our results suggest that inhibition of ERS and its downstream signaling mediators TXNIP and NLRP3 might represent novel therapeutic avenues for ameliorating microglia-mediated neuroinflammation in PD and other synucleinopathies.

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“…First, the peripheral inflammatory condition may play a role in the CNS pathology, or at least reflect the course of it, and second, inflammation may be associated with and, perhaps, underlie non-motor symptoms of PD (Williams-Gray et al, 2016). A more recent study questioned whether peripheral immune changes causally contribute to the progression of PD, reporting that serum levels of cytokines do not correlate with CSF content, and suggesting that central and peripheral cytokine levels may partially behave independently, and may be driven by different factors (Wijeyekoon et al, 2020). Additional evidence of a chronic and systemic inflammatory state comes from studies showing the altered profile of immune cell composition in the blood of PD patients as compared to healthy individuals, reporting for instance, an increase in monocyte number and a decrease in the CD4+ T cell to CD8 cytotoxic T cell ratio (Bas et al, 2001;Grozdanov et al, 2014).…”

Section: Parkinson's Diseasementioning

confidence: 99%

Repurposing Immunomodulatory Imide Drugs (IMiDs) in Neuropsychiatric and Neurodegenerative Disorders

et al. 2021

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Neuroinflammation represents a common trait in the pathology and progression of the major psychiatric and neurodegenerative disorders. Neuropsychiatric disorders have emerged as a global crisis, affecting 1 in 4 people, while neurological disorders are the second leading cause of death in the elderly population worldwide (WHO, 2001; GBD 2016 Neurology Collaborators, 2019). However, there remains an immense deficit in availability of effective drug treatments for most neurological disorders. In fact, for disorders such as depression, placebos and behavioral therapies have equal effectiveness as antidepressants. For neurodegenerative diseases such as Parkinson’s disease and Alzheimer’s disease, drugs that can prevent, slow, or cure the disease have yet to be found. Several non-traditional avenues of drug target identification have emerged with ongoing neurological disease research to meet the need for novel and efficacious treatments. Of these novel avenues is that of neuroinflammation, which has been found to be involved in the progression and pathology of many of the leading neurological disorders. Neuroinflammation is characterized by glial inflammatory factors in certain stages of neurological disorders. Although the meta-analyses have provided evidence of genetic/proteomic upregulation of inflammatory factors in certain stages of neurological disorders. Although the mechanisms underpinning the connections between neuroinflammation and neurological disorders are unclear, and meta-analysis results have shown high sensitivity to factors such as disorder severity and sample type, there is significant evidence of neuroinflammation associations across neurological disorders. In this review, we summarize the role of neuroinflammation in psychiatric disorders such as major depressive disorder, generalized anxiety disorder, post-traumatic stress disorder, and bipolar disorder, as well as in neurodegenerative disorders, such as Parkinson’s disease and Alzheimer’s disease, and introduce current research on the potential of immunomodulatory imide drugs (IMiDs) as a new treatment strategy for these disorders.

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Cerebrospinal Fluid Cytokines and Neurodegeneration‐Associated Proteins in Parkinson's Disease

Cited by 36 publications

References 18 publications

Mini Review: Correlations of Cognitive Domains With Cerebrospinal Fluid α-Synuclein Levels in Patients With Parkinson's Disease

Mini Review: Correlations of Cognitive Domains With Cerebrospinal Fluid α-Synuclein Levels in Patients With Parkinson's Disease

PKC Delta Activation Promotes Endoplasmic Reticulum Stress (ERS) and NLR Family Pyrin Domain-Containing 3 (NLRP3) Inflammasome Activation Subsequent to Asynuclein-Induced Microglial Activation: Involvement of Thioredoxin-Interacting Protein (TXNIP)/Thioredoxin (Trx) Redoxisome Pathway

Repurposing Immunomodulatory Imide Drugs (IMiDs) in Neuropsychiatric and Neurodegenerative Disorders

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