Neuroinflammation In Parkinson's Disease Research Articles

Key Non-coding Variants in Three Neuroapoptosis and Neuroinflammation-Related LncRNAs Are Protectively Associated with Susceptibility to Parkinson's Disease and Some of Its Clinical Features.

Research findings show that genetic susceptibility to sporadic Parkinson's disease (PD), a common neurodegenerative disorder, is determined through gene variation of loci involved in its development and pathogenesis. A growing body of strong evidence has revealed that dysfunction of long non-coding RNAs (lncRNAs) plays key roles in the pathogenesis and progression of PD through impairing neuronal signaling pathways, but little is known about the relationship between their variants and PD susceptibility. In this research, we intended to study the relationship between functional SNPs rs12826786C>T, rs3200401C>T, and rs6931097G>A in the key lncRNAs stimulating neuroapoptosis and neuroinflammation in PD, including HOTAIR, MALAT1, and lincRNA-P21, respectively, with susceptibility to PD as well as its clinical symptoms.The population of this study consisted of 240 individuals, including 120 controls and 120 cases, and the sample taken from them was peripheral blood. Genotyping of the target SNPs was done using PCR-RFLP. We found that the healthy individuals carry more T allele of MALAT1-rs3200401C>T compared to the patients (P= 0.019). Furthermore, it was observed that in the dominant genetic model, subjects with genotypes carrying the T allele have a lower risk of PD (OR= 0.530; CI= 0.296-0.950; P= 0.033). Regarding the lincRNA-P21-rs6931097G>A, we observed a significant protective relationship between its GA (OR= 0.144; CI= 0.030-0.680; P= 0.014) and AA (OR= 0.195; CI= 00.047-0.799; P= 0.023) genotypes with the manifestation of tremor and bradykinesia symptoms, respectively. Furthermore, the findings indicated that the minor TT genotype of HOTAIR-rs12826786C>T was significantly associated with a reduced risk of bradykinesia symptoms (OR= 0.147; CI= 0.039-0.555; P= 0.005). Collectively, these findings suggest that MALAT1-rs3200401C>T may be an important lncRNA SNP against the development of PD, while the other two SNPs show protective effects on the clinical manifestations of PD in a way that lincRNA-P21-rs6931097G>A has a protective effect against the occurrence of tremor and bradykinesia symptoms in PD patients, and HOTAIR -rs12826786C>T indicates a protective effect against the display of bradykinesia feature. Therefore, they can have valuable potential as biomarkers for clinical evaluations of this disease.

LRRK2 G2019S promotes astrocytic inflammation induced by oligomeric α-synuclein through NF-κB pathway

Parkinson's disease (PD) is characterized by the irreversible loss of dopaminergic neurons and the accumulation of α-synuclein in Lewy bodies. The oligomeric α-synuclein (O-αS) is the most toxic form of α-synuclein species, and it has been reported to be a robust inflammatory mediator. Mutations in Leucine-Rich Repeat Kinase 2 (LRRK2) are also genetically linked to PD and neuroinflammation. However, how O-αS and LRRK2 interact in glial cells remains unclear. Here, we reported that LRRK2 G2019S mutation, which is one of the most frequent causes of familial PD, enhanced the effects of O-αS on astrocytes both invivo and invitro. Meanwhile, inhibition of LRRK2 kinase activity could relieve the inflammatory effects of both LRRK2 G2019S and O-αS. We also demonstrated that nuclear factor κB (NF-κB) pathway might be involved in the neuroinflammatory responses. These findings revealed that inhibition of LRRK2 kinase activity may be a viable strategy for suppressing neuroinflammation in PD.

Large-scale rare variant burden testing in Parkinson's disease.

Parkinson's disease has a large heritable component and genome-wide association studies have identified over 90 variants with disease-associated common variants, providing deeper insights into the disease biology. However, there have not been large-scale rare variant analyses for Parkinson's disease. To address this gap, we investigated the rare genetic component of Parkinson's disease at minor allele frequencies <1%, using whole genome and whole exome sequencing data from 7184 Parkinson's disease cases, 6701 proxy cases and 51 650 healthy controls from the Accelerating Medicines Partnership Parkinson's disease (AMP-PD) initiative, the National Institutes of Health, the UK Biobank and Genentech. We performed burden tests meta-analyses on small indels and single nucleotide protein-altering variants, prioritized based on their predicted functional impact. Our work identified several genes reaching exome-wide significance. Two of these genes, GBA1 and LRRK2, have variants that have been previously implicated as risk factors for Parkinson's disease, with some variants in LRRK2 resulting in monogenic forms of the disease. We identify potential novel risk associations for variants in B3GNT3, AUNIP, ADH5, TUBA1B, OR1G1, CAPN10 and TREML1 but were unable to replicate the observed associations across independent datasets. Of these, B3GNT3 and TREML1 could provide new evidence for the role of neuroinflammation in Parkinson's disease. To date, this is the largest analysis of rare genetic variants in Parkinson's disease.

Microglia-specific knock-out of NF-κB/IKK2 increases the accumulation of misfolded α-synuclein through the inhibition of p62/sequestosome-1-dependent autophagy in the rotenone model of Parkinson's disease.

Parkinson's disease (PD) is the most common neurodegenerative movement disorder worldwide, with a greater prevalence in men than women. The etiology of PD is largely unknown, although environmental exposures and neuroinflammation are linked to protein misfolding and disease progression. Activated microglia are known to promote neuroinflammation in PD, but how environmental agents interact with specific innate immune signaling pathways in microglia to stimulate conversion to a neurotoxic phenotype is not well understood. To determine how nuclear factor kappa B (NF-κB) signaling dynamics in microglia modulate neuroinflammation and dopaminergic neurodegeneration, we generated mice deficient in NF-κB activation in microglia (CX3CR1-Cre::IKK2fl/fl ) and exposed them to 2.5 mg/kg/day of rotenone for 14 days, followed by a 14-day post-lesioning incubation period. We postulated that inhibition of NF-κB signaling in microglia would reduce overall inflammatory injury in lesioned mice. Subsequent analysis indicated decreased expression of the NF-κB-regulated autophagy gene, sequestosome 1 (p62), in microglia, which is required for targeting ubiquitinated α-synuclein (α-syn) for lysosomal degradation. Knock-out animals had increased accumulation of misfolded α-syn within microglia, despite an overall reduction in neurodegeneration. Interestingly, this occurred more prominently in males. These data suggest that microglia play key biological roles in the degradation and clearance of misfolded α-syn and this process works in concert with the innate immune response associated with neuroinflammation. Importantly, the accumulation of misfolded α-syn protein aggregates alone did not increase neurodegeneration following exposure to rotenone but required the NF-κB-dependent inflammatory response in microglia.

Post-inflammatory administration of N-acetylcysteine reduces inflammation and alters receptor levels in a cellular model of Parkinson's disease.

Parkinson's disease (PD) is a complex, multifactorial neurodegenerative disease with a prevalence of 1% over the age of 55. Neuropathological hallmarks of PD include the loss of dopaminergic neurons in the substantia nigra pars compacta and the accumulation of Lewy bodies that contain a variety of proteins and lipids including alpha-synuclein (α-syn). Although the formation of α-syn occurs intracellularly, it can also be found in the extracellular space where it can be taken up by neighboring cells. Toll-like receptor 2 (TLR2) is an immune system receptor that has been shown to recognize extracellular α-syn and modulate its uptake by other cells. Lymphocyte-activation gene 3 (LAG3), an immune checkpoint receptor, has also been proposed to play a role in extracellular α-syn internalization; however, a recent study has disputed this role. Internalized α-syn can trigger expression and secretion of inflammatory cytokines such as tumor necrosis factor alpha (TNF-α), interleukin (IL)-1β, IL-2, and IL-6 and induce neuroinflammation, apoptosis, and mitophagy that results in cellular death. In this study, we tested if N-acetylcysteine (NAC), an anti-inflammatory and anti-carcinogenic drug, can circumvent the detrimental effects of neuroinflammation and induce an anti-inflammatory response by modulating transcription and expression of TLR2 and LAG3 receptors. Cells overexpressing wild-type α-syn were treated with TNF-α to induce inflammation followed by NAC to inhibit the deleterious effects of TNF-α-induced inflammation and apoptosis. SNCA gene transcription and α-syn protein expression were validated by q-PCR and Western blot (WB), respectively. Cell viability was measured, and apoptosis was evaluated by WB and terminal deoxynucleotidyl transferase nick end labeling methods. Alterations in LAG3 and TLR2 receptor levels were evaluated by immunofluorescent labeling, WB, and q-PCR. TNF-α not only increased inflammation but also increased endogenous and overexpressed α-syn levels. NAC treatment decreased expression of TLR2 and increased transcription of LAG3 receptor and diminished inflammation-mediated toxicity and cell death. Here, we demonstrate that NAC can reduce neuroinflammation that occurs as a result of alpha-synuclein overexpression, via a TLR2-associated pathway, making it a promising candidate for therapeutic intervention. Further studies are needed to elucidate molecular mechanisms and pathways related to neuroinflammation in PD and to develop possible new therapeutic approaches to slow the clinical progression of PD.

Curcumin protects against rotenone-induced Parkinson's disease in mice by inhibiting microglial NLRP3 inflammasome activation and alleviating mitochondrial dysfunction

Parkinson's disease (PD) is a common neurodegenerative disorder worldwide. Currently, treatment options can only relieve symptoms but cannot prevent, slow, or halt the neurodegenerative process of PD. Much evidence has suggested that microglia-mediated neuroinflammation is involved in the pathophysiology of PD. As an anti-inflammatory agent, curcumin may exert a neuroprotective effect on PD. However, its mechanism has yet to be demonstrated clearly. Our results indicated that curcumin alleviated rotenone-induced behavioral defects, dopamine neuron loss, and microglial activation. Besides, the NF-κB signaling pathway, the NLRP3 inflammasome, and pro-inflammatory cytokines, including IL-18 and IL-1β, contributed to the microglia-mediated neuroinflammation in PD. Furthermore, Drp1-mediated mitochondrial fission causing mitochondrial dysfunction also had an etiological role in the process. This study suggests that curcumin protects against rotenone-induced PD by inhibiting microglial NLRP3 inflammasome activation and alleviating mitochondrial dysfunction in mice. Thus, curcumin may be a neuroprotective drug with promising prospects in PD.

Dopaminergic regulation of inflammation and immunity in Parkinson's disease: friend or foe?

Parkinson's disease (PD) is a neurodegenerative disease affecting 7-10 million people worldwide. Currently, there is no treatment available to prevent or delay PD progression, partially due to the limited understanding of the pathological events which lead to the death of dopaminergic neurons in the substantia nigra in the brain, which is known to be the cause of PD symptoms. The current available treatments aim at compensating dopamine (DA) deficiency in the brain using its precursor levodopa, dopaminergic agonists and some indirect dopaminergic agents. The immune system is emerging as a critical player in PD. Therefore, immune-based approaches have recently been proposed to be used as potential antiparkinsonian agents. It has been well-known that dopaminergic pathways play a significant role in regulating immune responses in the brain. Although dopaminergic agents are the primary antiparkinsonian treatments, their immune regulatory effect has yet to be fully understood. The present review summarises the current available evidence of the immune regulatory effects of DA and its mimics and discusses dopaminergic agents as antiparkinsonian drugs. Based on the current understanding of their involvement in the regulation of neuroinflammation in PD, we propose that targeting immune pathways involved in PD pathology could offer a better treatment outcome for PD patients.

Chapter 7 - Disease mechanisms as subtypes: Inflammation in Parkinson disease and related disorders

Neuroinflammation is a core feature of Parkinson disease (PD) and related disorders. Inflammation is detectable early in PD and persists throughout the disease state. Both the innate and the adaptive arms of the immune system are engaged in both human PD as well as in animal models of the disease. The upstream causes of PD are likely multiple and complex, which makes targeting of disease-modifying therapies based on etiological factors difficult. Inflammation is a broadly shared common mechanism and likely makes an important contribution to progression in most patients with manifest symptoms. Development of treatments targeting neuroinflammation in PD will require an understanding of the specific immune mechanisms which are active, their relative effects on both injury and neurorestoration, as well as the role of key variables likely to modulate the immune response: age, sex, the nature of the proteinopathies present, and the presence of copathologies. Studies characterizing the specific state of immune response in individuals and groups of people affected by PD will be essential to the development of targeted disease-modifying immunotherapies.

Repaglinide Elicits a Neuroprotective Effect in Rotenone-Induced Parkinson’s Disease in Rats: Emphasis on Targeting the DREAM-ER Stress BiP/ATF6/CHOP Trajectory and Activation of Mitophagy

Repaglinide, a meglitinide insulinotropic antidiabetic, was unraveled as a promising therapeutic agent for Huntington's disease by targeting the neuronal calcium sensor downstream regulatory element antagonist modulator (DREAM). However, its mechanistic profile in Parkinson's disease (PD) especially its impact on endoplasmic reticulum (ER) stress, mitophagy, and their interconnections is poorly elucidated. This study is the first to examine the neuroprotective potential of repaglinide in rotenone-induced PD in rats by exploring its effects on DREAM, BiP/ATF6/CHOP ER stress pathway, apoptosis, mitophagy/autophagy, oxidative stress, astrogliosis/microgliosis, and neuroinflammation. Male Wistar rats were randomly assigned to four groups: groups 1 and 2 received the vehicle or repaglinide (0.5 mg/kg/day p.o). Groups 3 and 4 received rotenone (1.5 mg/kg/48 h s.c) for 21 days; meanwhile, group 4 additionally received repaglinide (0.5 mg/kg/day p.o) for 15 days starting from day 11. Interestingly, repaglinide lessened striatal ER stress and apoptosis as evidenced by reduced BiP/ATF6/CHOP and caspase-3 levels; however, it augmented striatal DREAM mRNA expression. Repaglinide triggered the expression of the mitophagy marker PINK1 and the autophagy protein beclin1 and alleviated striatal oxidative stress through escalating catalase activity. In addition, repaglinide halted astrocyte/microglial activation and neuroinflammation in the striatum as expressed by reducing glial fibrillary acidic protein (GFAP) and ionized calcium-binding adaptor protein 1 (Iba1) immunostaining and decreasing interleukin (IL)-6 and IL-1β levels. Repaglinide restored striatum morphological alterations, intact neuron count, and neurobehavioral motor performance in rats examined by an open field, grip strength, and footprint gait analysis. Conclusively, repaglinide modulates the DREAM-ER stress BiP/ATF6/CHOP cascade, increases mitophagy/autophagy, inhibits apoptosis, and lessens oxidative stress, astrocyte/microglial activation, and neuroinflammation in PD.

Isoliquiritigenin inhibits microglia-mediated neuroinflammation in models of Parkinson's disease via JNK/AKT/NFκB signaling pathway.

Isoliquiritigenin (ISL) is a flavonoid with numerous pharmacological properties, including anti-inflammation, yet its role in Parkinson's disease (PD) with microglia-mediated neuroinflammation remains unknown. In this study, the effects of ISL on inhibiting microglia-mediated neuroinflammation in PD were evaluated in the 1-methyl-4-phenylpyridinium (MPTP)-induced mouse model of PD and in lipopolysaccharide (LPS)-stimulated BV-2 microglia. Our results showed that ISL prevented behavioral deficits and excessive microglial activation in MPTP-treated mice. Moreover, ISL was found to prevent the elevation of inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2), and mitigate the phosphorylation of c-Jun N-terminal protein kinase (JNK), protein kinase B (AKT), nuclear factor kappa light-chain enhancer of activated B cells (NFκB), and inhibitor of NFκB protein ɑ (IκBɑ) in the substantia nigra and striatum of MPTP-treated mice and LPS-stimulated BV-2 cells. Meanwhile, in LPS-stimulated BV-2 cells, ISL inhibited the production of inflammatory mediators such as interleukin (IL)-1β, IL-6 and tumor necrosis factor alpha (TNF-α). In addition, the agonist of JNK partly abolished the inhibitory effects of ISL in LPS-treated BV-2 cells. Our results demonstrated that ISL inhibits microglia-mediated neuroinflammation in PD models probably through deactivating JNK/AKT/NFκB signaling pathways. The novel findings suggest the therapeutic potential of ISL for microglia-mediated neuroinflammation in PD.

Mesencephalic astrocyte-derived neurotrophic factor (MANF) prevents the neuroinflammation induced dopaminergic neurodegeneration

BackgroundThe excessive activation of the microglia leads to the release of inflammatory factors that contribute to neuronal cell loss and neurodegeneration in Parkinson's Disease (PD). Mesencephalic astrocyte-derived neurotrophic factor (MANF) that belongs to a newly found neurotrophic factors (NTFs) family has been reported to promote neuronal survival in the PD models. However, the effects of the MANF on neuroinflammation in PD remain unclear. MethodsAAV8-MANF virus was constructed to determine whether the high expression of MANF can protect the neuroinflammation-induced dopaminergic neurodegeneration in rats with 6-OHDA-induced PD. Rotarod performance test, immunofluorescent staining and western bolt were employed to evaluate the behavioral dysfunction, dopaminergic neurodegeneration, microglia activation, and signal activation. 6-OHDA treated SH-SY5Y cells and LPS treated BV-2 cells were used as the in vitro model for MANF neuroprotective and neuroinflammation mechanisms. Cell vitality and apoptosis were evaluated with MTT, CCK-8 and flow cytometric analysis. The AKT/GSK3β-Nrf2 signaling and the TNF-α/IL6 expression were measured by Western Blot. ResultsOur findings indicated that the elevated MANF expression by the AAV8-MANF administration ameliorated the motor dysfunction and protected the dopaminergic neurons in the 6-OHDA treated rats. The upregulated CD11b in the rat SN caused by the 6-OHDA administration was significantly attenuated by the pretreatment of the AAV8-MANF. Furthermore, the levels of p-AKT, p-GSK3β, BCL-2, and Nrf-2 were upregulated by the high expression of the MANF. Under the oxidative stress of the 6-OHDA, the MANF significantly reduced the apoptotic effect of the TNF-α on the SH-SY5Y cells. In the LPS treated BV-2 cells, the MANF reduced the production of the TNF-α and IL-6, via enhancing the Nrf-2, p-Akt, p-GSK3β, and p-NF-κβ level. ConclusionsThese results suggested that the MANF prevented the dopaminergic neurodegeneration caused by the microglia activation in PD via activation of the AKT/GSK3β-Nrf-2 signaling axis.

Role of CD4&amp;#43; T Cells in Parkinson's Disease

Parkinson's disease (PD) is a progressive condition that affects both the central nervous system and other body parts that are controlled by the nervous system. PD is characterized by brain dopaminergic neurons loss and, at present, there are only symptomatic treatments available to alleviate the effects of the disease. With extensive research, new insights have led to defining PD as a multi-system disorder with immune dysfunction playing a dominant part in the disease pathogenesis as well as its progression. Neuroinflammation in PD leads to neurodegeneration, which is, in turn, regulated by the peripheral adaptive immunity, with CD4+ T cells being a significant player. Patients with PD have diverse CD4+ T cell phenotypes and functional profiles. These phenotypes vary, from being proinflammatory (Th1 and Th17) to anti-inflammatory (Th2 and Tregs). This report focuses on reviewing the expression of CD4+ T cells in PD and its role in the prognosis and treatment of PD.

A systematic review of molecular approaches that link mitochondrial dysfunction and neuroinflammation in Parkinson's disease.

Parkinson's disease (PD) is a chronic and progressive neurodegenerative disorder that affects 1% of the population worldwide. Etiology of PD is likely to be multi-factorial such as protein misfolding, mitochondrial dysfunction, oxidative stress, and neuroinflammation that contributes to the pathology of Parkinson's disease (PD), numerous studies have shown that mitochondrial dysfunction may play a key role in the dopaminergic neuronal loss. In multiple ways, the two most important are the activation of neuroinflammation and mitochondrial dysfunction, while mitochondrial dysfunction could cause neuroinflammation and vice versa. Thus, the mitochondrial proteins are the highly promising target for the development of PD. However, the limited amount of dopaminergic neurons prevented the detailed investigation of Parkinson's disease with regard to mitochondrial dysfunction. Both genetic and environmental factors are also associated with mitochondrial dysfunction and PD pathogenesis. The induction of PD by neurotoxins that inhibit mitochondrial complex I provide direct evidence linking mitochondrial dysfunction to PD. A decrease of mitochondrial complex I activity is observed in PD brain and in neurotoxin- or genetic factor-inducedin vitroandin vivomodels. Moreover, PINK1, Parkin, DJ-1 and LRRK2 mitochondrial PD gene products have important roles in mitophagy, a cellular process that clear damaged mitochondria.This review paper would discuss the evidence for the mitochondrial dysfunction and neuroinflammation in PD.

Early-start vs delayed-start donepezil against cognitive decline in Parkinson disease: a randomized clinical trial

ABSTRACT Background Cholinergic neurotransmission regulates neuroinflammation in Parkinson disease (PD). Research design and methods The authors conducted a delayed-start study of donepezil for cognitive decline in non-demented PD patients. The study consisted of a 96-week randomized placebo-controlled double-blind phase 1, followed by a 24-week donepezil extension phase 2. The primary outcome measure was a change in the Mini-Mental State Examination (MMSE) at week 120. Results A total of 98 patients were randomly allocated to the early-start (donepezil-to-donepezil) and delayed-start (placebo-to-donepezil) groups. Mean (SD) of the baseline MMSE was 27.6 (2.0) and 28.0 (2.1), respectively. MMSE change at week 120 was better in the early-start group than in the delayed-start group, but the difference was not significant. The MMSE declined in apolipoprotein ε4 carriers, but not in non-carriers, and the factor interaction (intervention × ε4 genotype) was highly significant (P < 0.001). Analyzed with the interaction, the difference was significant (group difference 1.95 [0.33 to 3.57], P = 0.018). The MMSE decline slope in phase 1 was significantly better in the early-start group than in the delayed-start group (P = 0.048). Conclusions Cognitive function deteriorated in ε4 carriers, but not in non-carriers, and early-start donepezil may postpone cognitive decline in the former.

Neuroprotective effects associated with immune modulation by selected lactic acid bacteria in a Parkinson's disease model.

Parkinson's disease (PD) is a neurodegenerative process that affects the motor function and involves an inflammatory response and B vitamin deficiencies. The aim of this study was to evaluate the effect of B-group vitamin-producing and immunomodulatory lactic acid bacteria (LAB) in a murine model of PD. The effect of Lactobacillus plantarum CRL 2130 (a riboflavin producer), Streptococcus thermophilus CRL 807 (an immunomodulatory strain), and Streptococcus thermophilus CRL 808 (a folate producer) were evaluated individually and as a mixture in mice injected with 1-methyl-4-fenil-1,2,3,6-tetrahidropiridina. Motor capacity, tyrosine hydrolase in the brain, and cytokine concentrations in serum and brain tissues were evaluated in 1-methyl-4-fenil-1,2,3,6-tetrahidropiridina-treated mice after bacterial supplementation. The mice receiving the selected LAB showed significantly improved motor skills compared with those that did not receive bacterial supplementation. When given the mixture of all 3 strains together, the animals had higher brain tyrosine hydrolase-positive cell counts, decreased inflammatory cytokines interleukin 6 and tumor necrosis factor alpha in serum, and increased antiinflammatory cytokine interleukin 10 in serum and brain tissues compared with animals that did not receive LAB supplementation. The results showed the potential of a selected LAB mixture to improve motor behavior and neuroinflammation in PD. This probiotic mixture could be used as an adjunct treatment in the control of PD.

Study of the Link Between Neuronal Death, Glial Response, and MAPK Pathway in Old Parkinsonian Mice

Background: Parkinson’s disease (PD) is described as an age-related neurodegenerative disorder. However, the vast majority of research is carried out using experimental models of young animals lacking the implications of the decline processes associated with aging. It has been suggested that several molecular pathways are involved in the perpetuation of the degeneration and the neuroinflammation in PD. Among others, mitogen-activated protein kinases (MAPKs) have been highly implicated in the development of PD, and regulating components of their activity are indicated as promising therapeutic targets.Methods: To further define how MAPKs expression is related to the glial response and neuronal cell death, Parkinsonism was induced under an acute regimen in old mice. Moreover, the sacrifice was carried out at different time points (4, 8, 24, and 48 h) after 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine hydrochloride (MPTP) injections to describe the early dynamic changes over time produced by the intoxication.Results: The results revealed that neuronal death increases as glial response increases in the nigrostriatal pathway. It was observed that both processes increase from 4 h in the ventral mesencephalon (VM), and neuronal death becomes significant at 48 h. In the striatum, they were significantly increased from 48 h after the MPTP administration compared with that in the control mice. Moreover, the p-ERK levels decrease, while phospho-p38 expression increases specifically in the striatum at 48 h after MPTP intoxication.Conclusions: The importance of these data lies in the possibility of elucidating the underlying mechanisms of neurodegenerative processes under aging conditions to provide knowledge for the search of solutions that slow down the progression of PD.

Molecular Signatures of Neuroinflammation Induced by αSynuclein Aggregates in Microglial Cells.

Alpha-synuclein (αSynAgg) are pathological hallmarks of Parkinson's disease (PD) and other synucleinopathies that induce microglial activation and immune-mediated neurotoxicity, but the molecular mechanisms of αSynAgg-induced immune activation are poorly defined. We performed quantitative proteomics by mass spectrometry coupled with PCR, immunohistochemical and functional validations studies to define the molecular characteristics of alpha synuclein mediated microglial activation. In mouse microglia, αSynAgg induced robust pro-inflammatory activation (increased expression of 864 genes including Irg1, Ifit1, and Pyhin) and increased nuclear proteins involved in RNA synthesis, splicing, and anti-viral defense mechanisms. Conversely, αSynAgg decreased expression several proteins (including Cdc123, Sod1, and Grn), which were predominantly cytosolic and involved in metabolic, proteasomal and lysosomal mechanisms. Pathway analyses and confirmatory in vitro studies suggested that αSynAgg partly mediates its effects via Stat3 activation. As predicted by our proteomic findings, we verified that αSynAgg induces mitochondrial dysfunction in microglia. Twenty-six proteins differentially expressed by αSynAgg were also identified as PD risk genes in genome-wide association studies (upregulated: Brd2, Clk1, Siglec1; down-regulated: Memo1, Arhgap18, Fyn, and Pgrn/Grn). We validated progranulin (PGRN) as a lysosomal PD-associated protein that is downregulated by αSynAgg in microglia in-vivo and is expressed by microglia in post-mortem PD brain, congruent with our in vitro findings.Conclusion: Together, proteomics approach both reveals novel molecular insights into αSyn-mediated neuroinflammation in PD and other synucleinopathies.

Niacin for Parkinson's disease

AbstractParkinson's disease (PD) is a neurodegenerative disease associated with progressive loss of motor function and cognitive decline occurring in 1% of the USA population. There is no cure for PD, and current treatment regimens are directed towards treating symptoms and not treating the underlying cause of the disease. Chronic neuroinflammation is associated with loss of neuronal cells, leading to motor and cognitive decline. Current clinical trials on drugs and nutraceuticals, such as coenzyme Q10 and niacin, are being carried out to delay progression and reduce damage by inflammatory molecules, such as reactive oxygen species and cytokines, in PD patients. In this review, we present available clinical trials and the role of niacin in reducing neuroinflammation in PD.

NF-κB-Mediated Neuroinflammation in Parkinson's Disease and Potential Therapeutic Effect of Polyphenols.

Different animal and human studies from last two decades in the case of Parkinson's disease (PD) have concentrated on oxidative stress due to increased inflammation and cytokine-dependent neurotoxicity leading to induction of dopaminergic (DA) degeneration pathway in the nigrostriatal region. Chronic inflammation, the principle hallmark of PD, forms the basis of neurodegeneration. Aging in association with activation of glia due to neuronal injury, perhaps because of immune alterations and genetic predispositions, leads to deregulation of inflammatory pathways premising the onset of PD. A family of inducible transcription factors, nuclear factor-κB (NF-κB), is found to show expression in various cells and tissues, such as microglia, neurons, and astrocytes which play an important role in activation and regulation of inflammatory intermediates during inflammation. Both canonical and non-canonical NF-κB pathways are involved in the regulation of the stimulated cells. During the prodromal/asymptomatic stage of age-associated neurodegenerative diseases (i.e., PD and AD), chronic neuroinflammation may act silently as the driver of neuronal dysfunction. Though research has provided an insight over age-related neurodegeneration in PD, elaborative role of NF-κB in neuroinflammation is yet to be completely understood and thus requires more investigation. Polyphenols, a group of naturally occurring compound in medicinal plants, have gained attention because of their anti-oxidative and anti-neuroinflammatory properties in neurodegenerative diseases. In this aspect, this review highlights the role of NF-κB and the possible therapeutic roles of polyphenols in NF-κB-mediated neuroinflammation in PD.

Diet in Parkinson's Disease: Critical Role for the Microbiome.

Background: Parkinson's disease (PD) is the most common movement disorder affecting up to 1% of the population above the age of 60 and 4–5% of those above the age of 85. Little progress has been made on efforts to prevent disease development or halt disease progression. Diet has emerged as a potential factor that may prevent the development or slow the progression of PD. In this review, we discuss evidence for a role for the intestinal microbiome in PD and how diet-associated changes in the microbiome may be a viable approach to prevent or modify disease progression.Methods: We reviewed studies demonstrating that dietary components/foods were related to risk for PD. We reviewed evidence for the dysregulated intestinal microbiome in PD patients including abnormal shifts in the intestinal microbiota composition (i.e., dysbiosis) characterized by a loss of short chain fatty acid (SCFA) bacteria and increased lipopolysaccharide (LPS) bacteria. We also examined several candidate mechanisms by which the microbiota can influence PD including the NLRP3 inflammasome, insulin resistance, mitochondrial function, vagal nerve signaling.Results: The PD-associated microbiome is associated with decreased production of SCFA and increased LPS and it is believed that these changes may contribute to the development or exacerbation of PD. Diet robustly impacts the intestinal microbiome and the Western diet is associated with increased risk for PD whereas the Mediterranean diet (including high intake of dietary fiber) decreases PD risk. Mechanistically this may be the consequence of changes in the relative abundance of SCFA-producing or LPS-containing bacteria in the intestinal microbiome with effects on intestinal barrier function, endotoxemia (i.e., systemic LPS), NLRP3 inflammasome activation, insulin resistance, and mitochondrial dysfunction, and the production of factors such as glucagon like peptide 1 (GLP-1) and brain derived neurotrophic factor (BDNF) as well as intestinal gluconeogenesis.Conclusions: This review summarizes a model of microbiota-gut-brain-axis regulation of neuroinflammation in PD including several new mechanisms. We conclude with the need for clinical trials in PD patients to test this model for beneficial effects of Mediterranean based high fiber diets.