Aideen M. Sullivan

The influence of microglia on the pathogenesis of Parkinson's disease

Parkinsons disease (PD) is characterised by degeneration of dopaminergic neurons in the substantia nigra pars compacta (SNpc). Inflammation may be associated with the neuropathology of PD due to the following accumulating evidence: excessive microglial activation and increased levels of the pro-inflammatory cytokines tumour necrosis factor-alpha and interleukin-1beta in the SNpc of patients with PD; the emergence of PD-like symptoms following influenza infection; the increased susceptibility to PD associated with bacterial vaginosis; the presence of inflammatory mediators and activators in animal models of PD; the ability of anti-inflammatory drugs to decrease susceptibility to PD; and the emerging possibility of the use of microglial activation inhibitors as a therapy in PD. In this review, we will discuss the role of inflammation in PD. We will focus on the influence of microglia in the pathogenesis of PD and discuss potential therapeutic interventions for PD, that target microglia.

Progress in Parkinson's disease—Where do we stand? ☆

Parkinsons disease was first described in 1817 by James Parkinson. It is one of the most common neurodegenerative disorders, affecting the nigrostriatal pathways involved in the control of movement. Since the introduction of L-DOPA as a therapy in the mid-1960s, clinical management of the symptoms has progressed, but, at present, it remains impossible to stop the disease progression or to restore lost functions. A better understanding of neurodegeneration and of midbrain neuronal development has allowed the development of new pharmaceutical compounds with neuroprotective properties and has shown the potential of neurone replacement therapies in Parkinsons disease. Even though major obstacles remain before these can be transferred to the clinic, the progress made in the last 10 years brings hope of improved therapies for Parkinsons disease. In this paper we review the current knowledge of Parkinsons disease including its etiology, some of the current symptomatic therapeutic modalities, and recent progress in neuroprotective and cell replacement therapies.

TGF-β and the regulation of neuron survival and death

Abstract Transforming growth factor-βs (TGF-βs) constitute a superfamily of multifunctional cytokines with important implications in morphogenesis, cell differentiation, and tissue remodeling. In the developing nervous system, TGF-β2 and -β3 occur in radial and astroglial cells as well as in many populations of postmitotic, differentiating neurons. TGF-β1 is restricted to the choroid plexus and meninges. In addition to functions related to glial cell maturation and performances, TGF-β2 and -β3 are important regulators of neuron survival. In contrast to neurotrophic factors, as for example, neurotrophins, TGF-βs are most likely not neurotrophic by themselves. However, they can dramatically increase the potency of select neurotrophins, fibroblast growth factor-2, ciliary neurotrophic factor, and glial cell line-derived neurotrophic factor (GDNF). In the case of GDNF, we have shown that GDNF fails to promote the survival of highly purified neuron populations in vitro unless it is supplemented with TGF-β. This also applies to the in vivo situation, where antibodies to all three TGF-β isoforms fully prevent the trophic effect of GDNF on axotomized, target-deprived neurons. In addition to the TGF-β isoforms -β2 and -β3, other members of the TGF-β superfamily are expressed in the nervous system having important roles in embryonic patterning, cell migration, and neuronal transmitter determination. We have cloned and expressed a novel TGF-β, named growth/differentiation factor-15 (GDF-15). GDF-15 is synthesized in the choroid plexus and released into the CSF, but also occurs in all regions investigated of the developing and adult brain. GDF-15 is a potent trophic factor for developing and 6-OHDA-lesioned midbrain dopaminergic neurons in vitro and in vivo, matching the potency of GDNF.

Growth/differentiation factor 5 and glial cell line-derived neurotrophic factor enhance survival and function of dopaminergic grafts in a rat model of Parkinson's disease

Growth/differentiation factor 5 is a member of the transforming growth factor β superfamily, which has neurotrophic and neuroprotective effects on dopaminergic neurons both in vitro and in vivo. Here we investigate the effects of growth/differentiation factor 5 on foetal mesencephalic grafts transplanted into a rat model of Parkinsons disease, and compare them with those of glial cell line‐derived neurotrophic factor. Mesencephalic tissue was suspended in solutions containing either growth/differentiation factor 5 or glial cell line‐derived neurotrophic factor prior to transplantation into the left striatum of rats with 6‐hydroxydopamine lesions of the left medial forebrain bundle. Both proteins enhanced graft‐induced compensation of amphetamine‐stimulated rotations. Positron emission tomography studies showed that both neurotrophins increased graft‐induced recovery of striatal binding of [11C]RTI‐121, a marker for dopaminergic nerve terminals. Post mortem analysis at 8 weeks after transplantation showed that both neurotrophins significantly increased the survival of grafted dopaminergic neurons. This study shows that growth/differentiation factor 5 is at least as effective as glial cell line‐derived neurotrophic factor in enhancing the survival and functional activity of mesencephalic grafts, and thus is an important candidate for use in the treatment of Parkinsons disease.

Tumour necrosis factor-α impairs neuronal differentiation but not proliferation of hippocampal neural precursor cells: Role of Hes1

Tumour necrosis factor-alpha (TNFalpha) is a pro-inflammatory cytokine, which influences neuronal survival and function yet there is limited information available on its effects on hippocampal neural precursor cells (NPCs). We show that TNFalpha treatment during proliferation had no effect on the percentage of proliferating cells prepared from embryonic rat hippocampal neurosphere cultures, nor did it affect cell fate towards either an astrocytic or neuronal lineage when cells were then allowed to differentiate. However, when cells were differentiated in the presence of TNFalpha, significantly reduced percentages of newly born and post-mitotic neurons, significantly increased percentages of astrocytes and increased expression of TNFalpha receptors, TNF-R1 and TNF-R2, as well as expression of the anti-neurogenic Hes1 gene, were observed. These data indicate that exposure of hippocampal NPCs to TNFalpha when they are undergoing differentiation but not proliferation has a detrimental effect on their neuronal lineage fate, which may be mediated through increased expression of Hes1.

A role for interleukin-1β in determining the lineage fate of embryonic rat hippocampal neural precursor cells.

Neurogenesis occurs in the hippocampus of the developing and adult brain due to the presence of multipotent stem cells and restricted precursor cells at different stages of differentiation. It has been proposed that they may be of potential benefit for use in cell transplantation approaches for neurodegenerative disorders and trauma. Prolonged release of interleukin-1β (IL-1β) from activated microglia has a deleterious effect on hippocampal neurons and is implicated in the impaired neurogenesis and cognitive dysfunction associated with aging, Alzheimers disease and depression. This study assessed the effect of IL-1β on the proliferation and differentiation of embryonic rat hippocampal NPCs in vitro. We show that IL-1R1 is expressed on proliferating NPCs and that IL-1β treatment decreases cell proliferation and neurosphere growth. When NPCs were differentiated in the presence of IL-1β, a significant reduction in the percentages of newly-born neurons and post-mitotic neurons and a significant increase in the percentage of astrocytes was observed in these cultures. These effects were attenuated by IL-1 receptor antagonist. These data reveal that IL-1β exerts an anti-proliferative, anti-neurogenic and pro-gliogenic effect on embryonic hippocampal NPCs, which is mediated by IL-1R1. The present results emphasise the consequences of an inflammatory environment during NPC development, and indicate that strategies to inhibit IL-1β signalling may be necessary to facilitate effective cell transplantation approaches or in conditions where endogenous hippocampal neurogenesis is impaired.

Midbrain dopaminergic neurons: a review of the molecular circuitry that regulates their development.

Dopaminergic (DA) neurons of the ventral midbrain (VM) play vital roles in the regulation of voluntary movement, emotion and reward. They are divided into the A8, A9 and A10 subgroups. The development of the A9 group of DA neurons is an area of intense investigation to aid the generation of these neurons from stem cell sources for cell transplantation approaches to Parkinsons disease (PD). This review discusses the molecular processes that are involved in the identity, specification, maturation, target innervation and survival of VM DA neurons during development. The complex molecular interactions of a number of genetic pathways are outlined, as well as recent advances in the mechanisms that regulate subset identity within the VM DA neuronal pool. A thorough understanding of the cellular and molecular mechanisms involved in the development of VM DA neurons will greatly facilitate the use of cell replacement therapy for the treatment of PD.

Parkinson's disease in the nuclear age of neuroinflammation

Chronic neuroinflammation is associated with the pathophysiology of Parkinsons disease, a movement disorder characterised by deterioration of the nigrostriatal system of the brain. Recent studies have yielded important insights into the regulation of inflammation by nuclear receptors, a superfamily of ligand-activated transcription factors. Certain nuclear receptors are also emerging as regulators of neurodegeneration, including the degeneration of dopaminergic neurons in Parkinsons disease, and the importance of transcriptional control in this process is becoming increasingly apparent. Here, we discuss the role of Nurr1, peroxisome proliferator-activated receptors (PPARs), retinoic acid receptors, and glucocorticoid receptors in neuroinflammatory processes that contribute to dopaminergic neuronal degeneration. We examine current evidence providing insight into the potential of these important players as therapeutic targets for Parkinsons disease.

BMP-Smad 1/5/8 signalling in the development of the nervous system

The transcription factors, Smad1, Smad5 and Smad8, are the pivotal intracellular effectors of the bone morphogenetic protein (BMP) family of proteins. BMPs and their receptors are expressed in the nervous system (NS) throughout its development. This review focuses on the actions of Smad 1/5/8 in the developing NS. The mechanisms by which these Smad proteins regulate the induction of the neuroectoderm, the central nervous system (CNS) primordium, and finally the neural crest, which gives rise to the peripheral nervous system (PNS), are reviewed herein. We describe how, following neural tube closure, the most dorsal aspect of the tube becomes a signalling centre for BMPs, which directs the pattern of the development of the dorsal spinal cord (SC), through the action of Smad1, Smad5 and Smad8. The direct effects of Smad 1/5/8 signalling on the development of neuronal and non-neuronal cells from various neural progenitor cell populations are then described. Finally, this review discusses the neurodevelopmental abnormalities associated with the knockdown of Smad 1/5/8.

Neurotrophic factors for the treatment of Parkinson's disease

Parkinsons disease (PD) is a common neurodegenerative disorder caused by the progressive degeneration of the nigrostriatal dopaminergic pathway. The resulting loss of dopamine neurotransmission is responsible for the symptoms of the disease. Available treatments are initially successful in treating PD symptoms; however, their long-term use is associated with complications and they cannot stop the neurodegeneration. Current research aims at developing new therapies to halt/reverse the neurodegenerative process, rather than treating symptoms. Neurotrophic factors are proteins critical for maintenance and protection of neurones in the developing and adult brain. Several neurotrophic factors have been investigated for their protective effects on dopaminergic neurones. Here we review some of the most promising factors and provide an update on their status in clinical trials.