Louise M. Collins

Contributions of central and systemic inflammation to the pathophysiology of Parkinson's disease

Idiopathic Parkinsons disease (PD) represents a complex interaction between the inherent vulnerability of the nigrostriatal dopaminergic system, a possible genetic predisposition, and exposure to environmental toxins including inflammatory triggers. Evidence now suggests that chronic neuroinflammation is consistently associated with the pathophysiology of PD. Activation of microglia and increased levels of pro-inflammatory mediators such as TNF-α, IL-1β and IL-6, reactive oxygen species and eicosanoids has been reported after post-mortem analysis of the substantia nigra from PD patients and in animal models of PD. It is hypothesised that chronically activated microglia secrete high levels of pro-inflammatory mediators which damage neurons and further activate microglia, resulting in a feed forward cycle promoting further inflammation and neurodegeneration. Moreover, nigrostriatal dopaminergic neurons are more vulnerable to pro-inflammatory and oxidative mediators than other cell types because of their low intracellular glutathione concentration. Systemic inflammation has also been suggested to contribute to neurodegeneration in PD, as lymphocyte infiltration has been observed in brains of PD patients and in animal models of PD, substantiating the current theory of a fundamental role of inflammation in neurodegeneration. We will examine the current evidence in the literature which offers insight into the premise that both central and systemic inflammation may contribute to neurodegeneration in PD. We will discuss the emerging possibility of the use of diagnostic tools such as imaging technologies for PD patients. Finally, we will present the immunomodulatory therapeutic strategies that are now under investigation and in clinical trials as potential neuroprotective drugs for PD.

Interleukin-1β contributes to dopaminergic neuronal death induced by lipopolysaccharide-stimulated rat glia in vitro

Inflammation is involved in the pathology of Parkinsons disease, a disorder characterised by degeneration of dopaminergic neurons. This study demonstrates that conditioned medium (CM) from lipopolysaccharide (LPS)-treated rat glial-enriched cortical cultures induced death of embryonic rat dopaminergic neurons in vitro, an effect which was additive to the toxicity of the neurotoxin 6-hydroxydopamine. Interleukin-1β (IL-1β) in the CM may mediate this neuronal death. IL-1R1 was found to be expressed on dopaminergic neurons. Blockade of IL-1R1 prevented CM-induced dopaminergic neuronal death. This study suggests that IL-1β in CM from LPS-stimulated glia contributes to dopaminergic neuronal death induced by glia-conditioned medium.

Exposure of foetal neural progenitor cells to IL-1β impairs their proliferation and alters their differentiation – a role for maternal inflammation?

J. Neurochem. (2012) 120, 964–973.

Canonical BMP-Smad signalling promotes neurite growth in rat midbrain dopaminergic neurons.

Ventral midbrain (VM) dopaminergic (DA) neurons project to the dorsal striatum via the nigrostriatal pathway to regulate voluntary movements, and their loss leads to the motor dysfunction seen in Parkinson’s disease (PD). Despite recent progress in the understanding of VM DA neurogenesis, the factors regulating nigrostriatal pathway development remain largely unknown. The bone morphogenetic protein (BMP) family regulates neurite growth in the developing nervous system and may contribute to nigrostriatal pathway development. Two related members of this family, BMP2 and growth differentiation factor (GDF)5, have neurotrophic effects, including promotion of neurite growth, on cultured VM DA neurons. However, the molecular mechanisms regulating their effects on DA neurons are unknown. By characterising the temporal expression profiles of endogenous BMP receptors (BMPRs) in the developing and adult rat VM and striatum, this study identified BMP2 and GDF5 as potential regulators of nigrostriatal pathway development. Furthermore, through the use of noggin, dorsomorphin and BMPR/Smad plasmids, this study demonstrated that GDF5- and BMP2-induced neurite outgrowth from cultured VM DA neurons is dependent on BMP type I receptor activation of the Smad 1/5/8 signalling pathway.

Mitogen-activated protein kinase phosphatase (MKP)-1 as a neuroprotective agent: promotion of the morphological development of midbrain dopaminergic neurons

A greater understanding of the mechanisms that promote the survival and growth of dopaminergic neurons is essential for the advancement of cell replacement therapies for Parkinson’s disease (PD). Evidence supports a role for the mitogen-activated protein kinase p38 in the demise of dopaminergic neurons, while mitogen-activated protein kinase phosphatase-1 (MKP-1), which negatively regulates p38 activity, has not yet been investigated in this context. Here, we show that MKP-1 is expressed in dopaminergic neurons cultured from E14 rat ventral mesencephalon (VM). When dopaminergic neurons were transfected to overexpress MKP-1, they displayed a more complex morphology than their control counterparts in vitro. Specifically, MKP-1-transfection induced significant increases in neurite length and branching with a maximum increase observed in primary branches. We demonstrate that inhibition of dopaminergic neurite growth induced by treatment of rat VM neurons with the dopaminergic neurotoxin 6-hydroxydopamine (6-OHDA) in vitro is mediated by p38 and is concomitant with a significant and selective decrease in MKP-1 expression in these neurons. We further show that overexpression of MKP-1 in dopaminergic neurons contributes to neuroprotection against the effects of 6-OHDA. Collectively, we report that MKP-1 can promote the growth and elaboration of dopaminergic neuronal processes and can help protect them from the neurotoxic effects of 6-OHDA. Thus, we propose that strategies aimed at augmenting MKP-1 expression or activity may be beneficial in protecting dopaminergic neurons and may provide potential therapeutic approaches for PD.

Class-IIa Histone Deacetylase Inhibition Promotes the Growth of Neural Processes and Protects Them Against Neurotoxic Insult

Small molecule histone deacetylase inhibitors (HDIs) hold much promise as pharmacological modifiers of the epigenetic status of the central nervous system (CNS), given their ability to cross the blood-brain barrier. This is particularly relevant given the lack of disease-modifying therapies for many neurodegenerative diseases and that epigenetic perturbations are increasingly recognised as playing a key role in their pathophysiology. In particular, emerging evidence in recent years has shown that epigenetic dysregulation may contribute to dopaminergic neuronal death in Parkinson’s disease. As a result, a number of pan-HDIs have been explored as potential neuroprotective agents for dopaminergic neurons. However, it is not known if the neuroprotective effects of pan-histone deacetylase (HDAC) inhibition are a general phenomenon or if these effects require inhibition of specific classes of HDACs. Here, we examine the ability of class-specific HDIs to promote neurite growth in a variety of cellular contexts. We find that MC1568, a class IIa-specific HDI, promotes neurite growth and arbourisation and protects neurite arbours against neurotoxic insult. Furthermore, we show that class IIa-specific HDAC inhibition results in activation of the canonical Smad signalling pathway, which is known to promote the survival and growth of midbrain dopaminergic neurons. These results demonstrate the potential of class IIa-specific HDIs as regulators of neuronal structure and suggest they should be examined in animal models of Parkinson’s disease as the next stage in rationalising their use as a potential therapy for this disorder.

Mitogen-Activated Protein Kinase Phosphatase (MKP)-1 in Nervous System Development and Disease.

Mitogen-activated protein kinase phosphatase (MKP)-1 provides a negative feedback mechanism for regulating mitogen-activated protein kinase (MAPK) activity and thus a variety of cellular processes such as proliferation, differentiation, growth and apoptosis. MKP-1 is established as a central regulator of a variety of functions in the immune, metabolic and cardiovascular systems, and it is now increasingly acknowledged as having a role to play in the nervous system. It has been implicated in regulating processes of neuronal cell development and death as well as in glial cell function. Reduced MKP-1 levels have been observed in models of neurological conditions including Huntington’s disease, multiple sclerosis, ischemia and cerebral hypoxia. It has also been suggested to have a role to play in psychiatric disorders such as major depressive disorder. Here, we discuss the role of MKP-1 in nervous system development and disease and examine current evidence providing insight into MKP-1 as a potential therapeutic target for various diseases of the central nervous system.

The neurite growth inhibitory effects of soluble TNFα on developing sympathetic neurons are dependent on developmental age

During development, the growth of neural processes is regulated by an array of cellular and molecular mechanisms which influence growth rate, direction and branching. Recently, many members of the TNF superfamily have been shown to be key regulators of neurite growth during development. The founder member of this family, TNFα can both promote and inhibit neurite growth depending on the cellular context. Specifically, transmembrane TNFα promotes neurite growth, while soluble TNFα inhibits it. While the growth promoting effects of TNFα are restricted to a defined developmental window of early postnatal development, whether the growth inhibitory effects of soluble TNFα occur throughout development is unknown. In this study we used the extensively studied, well characterised neurons of the superior cervical ganglion to show that the growth inhibitory effects of soluble TNFα are restricted to a specific period of late embryonic and early postnatal development. Furthermore, we show that this growth inhibitory effect of soluble TNFα requires NF-κB signalling at all developmental stages at which soluble TNFα inhibits neurite growth. These findings raise the possibility that increases in the amount of soluble TNFα in vivo, for example as a result of maternal inflammation, could negatively affect neurite growth in developing neurons at specific stages of development.

Nociceptin/Orphanin FQ Inhibits the Survival and Axon Growth of Midbrain Dopaminergic Neurons Through a p38-MAPK Dependent Mechanism

Nociceptin/orphanin FQ (N/OFQ) is an opioid-like neuropeptide that binds and signals through a G-protein-coupled receptor called the N/OFQ peptide (NOP) receptor. N/OFQ and the NOP receptor are expressed in the midbrain and have been implicated in the pathogenesis of Parkinson’s disease (PD). Genetic removal of the N/OFQ precursor partially protects midbrain dopaminergic neurons from 1-methyl-4-phenylpyridine-induced toxicity, suggesting that endogenous N/OFQ may be detrimental to dopaminergic neurons. However, whether N/OFQ directly affects the survival and growth of dopaminergic neurons is unknown. Here, we show that N/OFQ has a detrimental effect on the survival of dopaminergic neurons and the growth of their axons in primary cultures of the E14 rat ventral mesencephalon. N/OFQ potentiates the effects of the neurotoxins 6-hydroxydopamine and 1-methyl-4-phenylpyridinium through p38-MAPK signalling. We also show that like α-synuclein, there is a significant reduction in N/OFQ messenger RNA (mRNA) expression in the midbrain of patients with Parkinson’s disease. These results demonstrate for the first time that N/OFQ is detrimental to the survival and growth of dopaminergic neurons and that its expression is altered in the midbrain of patients with Parkinson’s disease.

Inflammation in Parkinson’s Disease: Causes and Consequences

Parkinson’s disease (PD) is the second most common progressive neurodegenerative disorder after Alzheimer’s disease (AD) with a prevalence of 0.5-1% among persons older than 65 years of age (Toulouse & Sullivan, 2008). The incidence increases to 2.6% in persons aged 85 and older, and has a mean age of onset of 55 years. Statistics released in 1990 from a unique global study carried out by the World Health Organisation, suggest that there are approximately 4 million PD patients worldwide. However, despite intensive research, the aetiology of this neurodegenerative disease still remains unclear and despite substantial efforts, a cure remains elusive. This, coupled with the increasing aging demographics, makes the importance of research into PD imperative, and the development of novel drug treatments a primary aim, both for economic and humanitarian purposes. The disease is a chronic, progressive neurodegenerative motor disorder, resulting in the selective loss of dopaminergic (DA) neurons within the substantia nigra (SN) pars compacta (pc) of the midbrain. As the disease progresses there is gradual circuitry degeneration within the nigrostriatal pathway, producing motor, cognitive and psychiatric symptoms (Braak et al., 2003). Lewy bodies are classified as the focal pathological hallmark of PD and their presence is necessary for the post-mortem diagnosis of the disease. They are not unique to PD however and are also found in other diseases such as dementia with Lewy Bodies and diffuse Lewy Body disease (Braak et al., 2003). PD can be further characterised by the presence of an accumulation of activated microglia within the SNpc (McGeer et al., 1988). PD exists in many forms and can be classified into both familial and idiopathic (also referred to as sporadic) forms, with epidemiological studies indicating approximately 5-10% of cases as being familial, and 90-95% as idiopathic (Tomiyama et al., 2008). Familial PD can be transmitted in an autosomal dominant (AD-PD) or recessive fashion (AR-PD). The study of genetic forms of PD has led to a better understanding of the underlying molecular mechanisms occurring during the disease progression. To date, six genes (SNCA, LRRK2, PRKN, DJ-1, PINK1 and ATP13A2) have been implicated in familial forms of PD (Bekris et al., 2010). In contrast to idiopathic PD, the genetic forms of this disease display a significantly younger age of onset and a shorter disease duration (Pankratz & Foroud, 2007). Despite this, patients with the autosomal dominant form of the disease have similar clinical and pathological features to those with idiopathic PD. In idiopathic PD, environmental factors such as toxins, free radicals and inflammation have been considered the most likely