Inflammation in Parkinson’s Disease: Mechanisms and Therapeutic Implications

Pajares, Marta; Rojo, Ana I.; Manda, Gina; Boscá, Lisardo; Cuadrado, Antonio

doi:10.3390/cells9071687

Cited by 454 publications

(354 citation statements)

References 256 publications

Supporting

Mentioning

296

Contrasting

Unclassified

Order By: Relevance

“…It is known that neuroinflammation induced by activation of astrocytes and microglia with subsequent dysfunction of endotelhial cells contributes to PD pathogenesis. Besides central inflammation, peripheral proinflammatory profile with altered CD4 + /CD8 + T cells ratios and Treg cells might facilitate neurodegeneration 77 . Several transcriptome studies that were performed in different platforms with different tissues have highlighted the importance of inflammatory pathways in PD pathogenesis 78 .…”

Section: Discussionmentioning

confidence: 99%

Inflammation and regulatory T cell genes are differentially expressed in peripheral blood mononuclear cells of Parkinson’s disease patients

Karaaslan

Kahraman

Şanlı

et al. 2021

Sci Rep

View full text Add to dashboard Cite

Our aim was to identify the differentially expressed genes (DEGs) in peripheral blood mononuclear cells (PBMC) of Parkinson’s disease (PD) patients and healthy controls by microarray technology and analysis of related molecular pathways by functional annotation. Thirty PD patients and 30 controls were enrolled. Agilent Human 8X60 K Oligo Microarray was used for gene level expression identification. Gene ontology and pathway enrichment analyses were used for functional annotation of DEGs. Protein–protein interaction analyses were performed with STRING. Expression levels of randomly selected DEGs were quantified by real time quantitative polymerase chain reaction (RT-PCR) for validation. Flow cytometry was done to determine frequency of regulatory T cells (Tregs) in PBMC. A total of 361 DEGs (143 upregulated and 218 downregulated) were identified after GeneSpring analysis. DEGs were involved in 28 biological processes, 12 cellular components and 26 molecular functions. Pathway analyses demonstrated that upregulated genes mainly enriched in p53 (CASP3, TSC2, ATR, MDM4, CCNG1) and PI3K/Akt (IL2RA, IL4R, TSC2, VEGFA, PKN2, PIK3CA, ITGA4, BCL2L11) signaling pathways. TP53 and PIK3CA were identified as most significant hub proteins. Expression profiles obtained by RT-PCR were consistent with microarray findings. PD patients showed increased proportions of CD49d+ Tregs, which correlated with disability scores. Survival pathway genes were upregulated putatively to compensate neuronal degeneration. Bioinformatics analysis showed an association between survival and inflammation genes. Increased CD49d+ Treg ratios might signify the effort of the immune system to suppress ongoing neuroinflammation.

show abstract

Section: Discussionmentioning

confidence: 99%

Inflammation and regulatory T cell genes are differentially expressed in peripheral blood mononuclear cells of Parkinson’s disease patients

Karaaslan

Kahraman

Şanlı

et al. 2021

Sci Rep

View full text Add to dashboard Cite

show abstract

“…169 In addition, aberrant α-Syn is transferred from neurons to microglia and astrocytes, triggering a proinflammatory response. 170,171 α-Syn accumulation by GCase inhibition in mice induces complement C1q 172 expression required for microglial phagocytosis. Intriguingly, genetic Gba1 ablation in dopaminergic mouse neurons activates microglia without neurodegeneration.…”

Section: Cholesterol In Neuroinflammationmentioning

confidence: 99%

The Role of Cholesterol in α‐Synuclein and Lewy Body Pathology in GBA1 Parkinson's Disease

2020

View full text Add to dashboard Cite

A BS TRACT: Parkinson's disease (PD) is a progressive neurodegenerative disease where dopaminergic neurons in the substantia nigra are lost, resulting in a decrease in striatal dopamine and, consequently, motor control. Dopaminergic degeneration is associated with the appearance of Lewy bodies, which contain membrane structures and proteins, including α-synuclein (α-Syn), in surviving neurons. PD displays a multifactorial pathology and develops from interactions between multiple elements, such as age, environmental conditions, and genetics. Mutations in the GBA1 gene represent one of the major genetic risk factors for PD. This gene encodes an essential lysosomal enzyme called β-glucocerebrosidase (GCase), which is responsible for degrading the glycolipid glucocerebroside into glucose and ceramide. GCase can generate glucosylated cholesterol via transglucosylation and can also degrade the sterol glucoside. Although the molecular mechanisms that predispose an individual to neurodegeneration remain unknown, the role of cholesterol in PD pathology deserves consideration. Disturbed cellular cholesterol metabolism, as reflected by accumulation of lysosomal cholesterol in GBA1-associated PD cellular models, could contribute to changes in lipid rafts, which are necessary for synaptic localization and vesicle cycling and modulation of synaptic integrity. α-Syn has been implicated in the regulation of neuronal cholesterol, and cholesterol facilitates interactions between α-Syn oligomers. In this review, we integrate the results of previous studies and describe the cholesterol landscape in cellular homeostasis and neuronal function. We discuss its implication in α-Syn and Lewy body pathophysiological mechanisms underlying PD, focusing on the role of GCase and cholesterol.

show abstract

“…DLB is caused by the abnormal accumulation of α-syn in neurons, called Lewy bodies (LBs) and Lewy neurites (LNs; Cummings, 2004;Walker et al, 2015). Most DLB cases occur sporadically, but several papers have suggested that DLB has a genetic cause, such as APOE, SNCA, and LRRK2 (Walker et al, 2015;Orme et al, 2018). Excessive accumulation of α-syn in DLB is associated with the loss and dysfunction of dopaminergic neurons and cholinergic neurons (Tiraboschi et al, 2000;Gomperts, 2016).…”

Section: Dlb (Dementia With Lewy Bodies)mentioning

confidence: 99%

“…Many pathological features of PD, such as mitochondrial dysfunction ( Park et al, 2018 ; Wang X.L. et al, 2020 ), neuroinflammation ( Wang et al, 2015 ; Pajares et al, 2020 ), ER stress ( Colla, 2019 ), and impaired protein quality control ( Cook and Petrucelli, 2009 ; Sala et al, 2016 ), can lead to neuronal toxicity. α-Synucleinopathy features the accumulation of aggregated α-syn in neuronal and glial cells ( McCann et al, 2014 ).…”

Section: Neurodegenerative Disorders Associated With α-Synucleinopathmentioning

confidence: 99%

The Role of Glial Mitochondria in α-Synuclein Toxicity

Jeon

Kwon

et al. 2020

Front. Cell Dev. Biol.

View full text Add to dashboard Cite

The abnormal accumulation of alpha-synuclein (α-syn) aggregates in neurons and glial cells is widely known to be associated with many neurodegenerative diseases, including Parkinson’s disease (PD), Dementia with Lewy bodies (DLB), and Multiple system atrophy (MSA). Mitochondrial dysfunction in neurons and glia is known as a key feature of α-syn toxicity. Studies aimed at understanding α-syn-induced toxicity and its role in neurodegenerative diseases have primarily focused on neurons. However, a growing body of evidence demonstrates that glial cells such as microglia and astrocytes have been implicated in the initial pathogenesis and the progression of α-Synucleinopathy. Glial cells are important for supporting neuronal survival, synaptic functions, and local immunity. Furthermore, recent studies highlight the role of mitochondrial metabolism in the normal function of glial cells. In this work, we review the complex relationship between glial mitochondria and α-syn-mediated neurodegeneration, which may provide novel insights into the roles of glial cells in α-syn-associated neurodegenerative diseases.

show abstract

Inflammation in Parkinson’s Disease: Mechanisms and Therapeutic Implications

Cited by 454 publications

References 256 publications

Inflammation and regulatory T cell genes are differentially expressed in peripheral blood mononuclear cells of Parkinson’s disease patients

Inflammation and regulatory T cell genes are differentially expressed in peripheral blood mononuclear cells of Parkinson’s disease patients

The Role of Cholesterol in α‐Synuclein and Lewy Body Pathology in GBA1 Parkinson's Disease

The Role of Glial Mitochondria in α-Synuclein Toxicity

Contact Info

Product

Resources

About