Inflammatory Mechanisms of Neurodegeneration in Toxin-Based Models of Parkinson's Disease

Litteljohn, Darcy; Mangano, Emily; Clarke, Melanie; Bobyn, Jessica; Moloney, Kerry; Hayley, Shawn

doi:10.4061/2011/713517

Cited by 66 publications

(106 citation statements)

References 206 publications

(229 reference statements)

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“…Moreover, there is substantial evidence that microglia are activated in mouse, rat and non-human primate models of PD prior to frank neuron death. Collectively, these observations support the hypothesis that αSyn is released early in the disease and, acting as an endogenous disease-related signal, it activates microglia to release pro-inflammatory molecules, such as TNF-α and IL-1β, which are detrimental to dopamine neurons [24], [25]. The progressive death of the latter is expected to be responsible for further αSyn release, thus amplifying the neurodegenerative process [26].…”

Section: Introductionsupporting

confidence: 69%

Triggering of Inflammasome by Aggregated α–Synuclein, an Inflammatory Response in Synucleinopathies

et al. 2013

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Parkinson’s disease (PD) is one of the most common neurodegenerative diseases. It is characterized by the loss of dopaminergic neurons in the substantia nigra pars compacta of the brain. Another feature is represented by the formation in these cells of inclusions called Lewy bodies (LB), principally constituted by fibrillar α-synuclein (αSyn). This protein is considered a key element in the aetiology of a group of neurodegenerative disorders termed synucleinopathies, which include PD, but the cellular and molecular mechanisms involved are not completely clear. It is established that the inflammatory process plays a crucial role in the pathogenesis and/or progression of PD; moreover, it is known that aggregated αSyn, released by neurons, activates microglia cells to produce pro-inflammatory mediators, such as IL-1β. IL-1β is one of the strongest pro-inflammatory cytokines; it is produced as an inactive mediator, and its maturation and activation requires inflammasome activation. In particular, the NLRP3 inflammasome is activated by a wide variety of stimuli, among which are crystallized and particulate material. In this work, we investigated the possibility that IL-1β production, induced by fibrillar αSyn, is involved the inflammasome activation. We demonstrated the competence of monomeric and fibrillar αSyn to induce synthesis of IL-1β, through TLR2 interaction; we found that the secretion of the mature cytokine was a peculiarity of the fibrillated protein. Moreover, we observed that the secretion of IL-1β involves NLRP3 inflammasome activation. The latter relies on the phagocytosis of fibrillar αSyn, followed by increased ROS production and cathepsin B release into the cytosol. Taken together, our data support the notion that fibrillar αSyn, likely released by neuronal degeneration, acts as an endogenous trigger inducing a strong inflammatory response in PD.

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Section: Introductionsupporting

confidence: 69%

Triggering of Inflammasome by Aggregated α–Synuclein, an Inflammatory Response in Synucleinopathies

et al. 2013

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“…First identified by James Parkinson in 1817, who wrote an essay on the shaking palsy for the description of disease. Currently, it represents the second most common neurodegenerative disorder, after Alzheimer's disease [1, 2], and affects approximately 6 million people worldwide [3]. Patients exhibit a range of clinical symptoms, with the most common affecting motor function, including the development of resting tremor, rigidity, akinesia, bradykinesia and postural instability.…”

Section: Introductionmentioning

confidence: 99%

A Synopsis on the Role of Tyrosine Hydroxylase in Parkinson’s Disease

Tabrez¹,

Jabir²,

Shakil³

et al. 2012

CNSNDDT

128

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Parkinson's disease (PD) is a common chronic progressive neurodegenerative disorder in elderly people. A consistent neurochemical abnormality in PD is degeneration of dopaminergic neurons in substantia nigra pars compacta, leading to a reduction of striatal dopamine (DA) levels. As tyrosine hydroxylase (TH) catalyses the formation of L-dihydroxyphenylalanine (L-DOPA), the rate-limiting step in the biosynthesis of DA, the disease can be considered as a TH-deficiency syndrome of the striatum. Problems related to PD usually build up when vesicular storage of DA is altered by the presence of either α-synuclein protofibrils or oxidative stress. Phosphorylation of three physiologically-regulated specific sites of N-terminal domain of TH is vital in regulating its kinetic and protein interaction. The concept of physiological significance of TH isoforms is another interesting aspect to be explored further for a comprehensive understanding of its role in PD. Thus, a logical and efficient strategy for PD treatment is based on correcting or bypassing the enzyme deficiency by the treatment with L-DOPA, DA agonists, inhibitors of DA metabolism or brain grafts with cells expressing a high level of TH. Neurotrophic factors are also attracting the attention of neuroscientists because they provide the essential neuroprotective and neurorestorative properties to the nigrostriatal DA system. PPAR-γ, a key regulator of immune responses, is likewise a promising target for the treatment of PD, which can be achieved by the use of agonists with the potential to impact the expression of pro- and anti-inflammatory cytokines at the transcriptional level in immune cells via expression of TH. Herein, we review the primary biochemical and pathological features of PD, and describe both classical and developing approaches aimed to ameliorate disease symptoms and its progression.

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“…Although neuroinflammation has been implicated in MPTP-induced neurotoxicity in the brain [33], MPTP-induced inflammatory responses in the spinal cord have not been extensively evaluated. The effects of MPTP on glial cells were studied in ventral regions of cervical and lumbar spinal cord samples using immunofluorescent staining with markers of astrocytes (GFAP), microglia (Iba-1) and infiltration of peripheral macrophages (ED-2).…”

Section: Resultsmentioning

confidence: 99%

Inhibition of Calpain Activation Protects MPTP-Induced Nigral and Spinal Cord Neurodegeneration, Reduces Inflammation, and Improves Gait Dynamics in Mice

et al. 2015

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Parkinson’s disease (PD) is the most common neurodegenerative movement disorder, resulting in dopaminergic (DA) neuronal loss in the substantia nigra pars compacta (SNpc) and damage to extranigral spinal cord neurons. Current therapies do not prevent the disease progression. Hence, developing efficacious therapeutic strategies for treatment of PD is of utmost importance. The goal of this study is to delineate the involvement of calpain-mediated inflammation and neurodegeneration in SN and spinal cord in MPTP-induced parkinsonian mice (C57BL/6N), thereby elucidating potential therapeutic target(s). Increased calpain expression was found localized to tyrosine hydroxylase (TH+) neurons in SN alongside with significantly increased TUNEL positive neurons in SN and spinal cord neurons in MPTP mice. Inflammatory markers Cox-2, caspase-1, and NOS-2 were significantly up-regulated in MPTP mice spinal cord as compared to control. These parameters correlated with the activation of astrocytes, microglia, infiltration of CD4+ / CD8+ T cells and macrophages. We found that subpopulations of CD4+ cells (Th1 & Tregs) were differentially expanded in MPTP mice, which could be regulated by inhibition of calpain with the potent inhibitor calpeptin. Pre-treatment with calpeptin (25 μg/kg, i.p.) attenuated glial activation, T cell infiltration, nigral dopaminergic degeneration in SN, and neuronal death in spinal cord. Importantly, calpeptin ameliorated MPTP-induced altered gait parameters (e.g. reduced stride length and increased stride frequency) as demonstrated by analyses of spatio-temporal gait indices using ventral plane videography. These findings suggest that calpain plays a pivotal role in MPTP-induced nigral and extranigral neurodegenerative processes, and may be a valid therapeutic target in PD.

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Inflammatory Mechanisms of Neurodegeneration in Toxin-Based Models of Parkinson's Disease

Cited by 66 publications

References 206 publications

Triggering of Inflammasome by Aggregated α–Synuclein, an Inflammatory Response in Synucleinopathies

Triggering of Inflammasome by Aggregated α–Synuclein, an Inflammatory Response in Synucleinopathies

A Synopsis on the Role of Tyrosine Hydroxylase in Parkinson’s Disease

Inhibition of Calpain Activation Protects MPTP-Induced Nigral and Spinal Cord Neurodegeneration, Reduces Inflammation, and Improves Gait Dynamics in Mice

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