Oxidative Stress and Redox Signalling in Parkinsons Disease

Rodrigo Franco, Jonathan A Doorn, Jean-Christophe Rochet, Rodrigo Franco, Jonathan A Doorn, Jean-Christophe Rochet

• Publisher: Royal Society of Chemistry
• Year: 2017
• ISBN:
  9781788011914
• Edition: 1
• Topic: Médecine
• Subtopic: Toxicologie

Parkinson's Disease is the second most common neurodegenerative disorder affecting millions of people worldwide. In order to find neuroprotective strategies, a clear understanding of the mechanisms involved in the dopaminergic death of cells that progresses the disease is needed. Oxidative stress can be defined as an imbalance between the production of reactive species and the ability to detoxify them and their intermediates or by-products. Oxidative damage to lipids, proteins, and DNA has been detected in autopsies from individuals with Parkinson's Disease and so links can be made between oxidative stress and Parkinson's Disease pathogenesis.
This book provides a thorough review of the mechanisms by which oxidative stress and redox signalling mediate Parkinson's Disease. Opening chapters bring readers up to speed on basic knowledge regarding oxidative stress and redox signalling, Parkinson's Disease, and neurodegeneration before the latest advances in this field are explored in detail. Topics covered in the following chapters include the role of mitochondria, dopamine metabolism, metal homeostasis, inflammation, DNA-damage and thiol-signalling. The role of genetics and gene-environment interactions are also explored before final chapters discuss the identification of potential biomarkers for diagnosis and disease progression and the future of redox/antioxidant based therapeutics.
Written by recognized experts in the field, this book will be a valuable source of information for postgraduate students and academics, clinicians, toxicologists and risk assessment groups. Importantly, it presents the current research that might later lead to redox or antioxidant – based therapeutics for Parkinson's disease.

CHAPTER 1

Etiology and Pathogenesis of Parkinson’s Disease

BRIANA R. DE MIRANDA^a AND J. TIMOTHY GREENAMYRE^a

^a Pittsburgh Institute for Neurodegenerative Diseases and Department of Neurology, University of Pittsburgh, Pittsburgh, PA 15260, USA
[email protected]

1.1 Introduction

Parkinson’s disease (PD) is the second most common neurodegenerative disorder (after Alzheimer’s disease), and it is estimated that PD affects approximately 10 million individuals worldwide, though many cases may go undiagnosed. With the growth of aging populations, it is estimated that PD will nearly double in incidence over the next 25 years, representing a major social and economic burden to provide long-term treatment and care for those affected.¹ This pressing concern has focused increased attention on the field of neurodegeneration, and while laboratory discoveries have begun translation into the clinic, one critical issue persists; the underlying causes of this progressive disorder remain, for the most part, unidentified. Inherited forms of PD strongly correspond to known genetic mutations in proteins involved with mitochondrial function, oxidative stress, and protein degradation pathways. However, inherited forms of PD only account for about 10% of PD cases, and sporadic PD has a much lower association with single gene mutations that are readily identified by specific protein dysfunction.^2,3 The pathogenesis of both familial and idiopathic PD involves several components; the gross manifestations of the disorder, the underlying neuronal death and cellular pathology, the molecular mechanisms behind progressive degeneration, and the genetic or environmental dysregulation of proteins responsible for cellular dysfunction.

Currently, no curative or ‘disease-modifying’ therapy is available to slow or stop the inevitable and inexorable progression of PD. While symptomatic treatment options are available, as the disease progresses and medication doses rise, the tolerability of PD drugs may decrease and side effects often become problematic. In order to develop therapeutic strategies that prevent the progressive loss of dopamine neurons, a clear understanding of the mechanisms behind cell death in PD must be elucidated. Many putative pathological mechanisms in PD can be linked to common pathways that converge on the mitochondrial production of oxidative stress. Here, the pathogenesis of oxidative stress in PD is examined in the context of the cellular pathology observed in the disease.

1.2 Clinical Manifestations of Parkinson’s Disease

The motor signs and symptoms of PD – bradykinesia, resting tremor, rigidity, and postural instability – together with the patient’s history, are the primary means for identifying the disorder, and current guidelines require two of the four main signs of the disease to be present, typically presenting with asymmetrical onset.⁴ Most individuals are diagnosed over the age of 45, with only a small percentage (10%) of cases considered early-onset (under the age of 45).⁴ Accompanying these movement deficits are non-motor symptoms of PD, such as decreased GI motility, loss of olfactory function, sleep disorders, and cognitive or behavioral changes.⁵ Non-motor symptoms often occur prior to the onset of motor symptoms, though their presence alone has proven unreliable for detecting PD.⁶ Motor symptoms of PD occur when there is approximately 80% loss of striatal dopamine levels, indicating that significant cell death and damage has occurred prior to emergence of visible symptoms of the disease.^7,8 This ‘silent’ period of pathogenesis is extremely problematic as it narrows the window for neuroprotective therapeutic intervention to the period after clinical diagnosis.

There is no definitive test for PD outside of the diagnostic criteria in the clinic and the response of a patient to levodopa (L-DOPA), which is the precursor of dopamine and the most efficacious symptomatic treatment for the disease.⁹ Unfortunately, maintenance with L-DOPA and dopamine receptor agonists has limitations. On the one hand, dopamine mimetics are useful at abating many of the symptoms in PD such as bradykinesia, rigidity, and tremor, while on the other hand they contribute to a host of iatrogenic symptoms, including dyskinesias, ‘wearing off’ effects, and hallucinations.¹⁰ In addition, treatment with dopamine agonists may exacerbate impulse control disorders, such as excessive gambling and reward-seeking behavior.^11,12 There are also indications that dopamine-replacement therapy itself contributes to cellular toxicity, possibly enhancing the progressive loss of neurons associated with PD.¹³ Several small molecule therapies aimed at inhibiting the progression of PD have entered the pipeline for novel drug development, many of which are anti-inflammatory therapies targeted at limiting oxidative stress.¹⁴ It is critical to note, however, that no compound has been proven successful in Phase III clinical trials for this purpose, and the pursuit for new therapeutic strategies continues.

1.3 Neuropathology

Underlying many of the motor symptoms of PD is the selective loss of dopaminergic neurons of the substantia nigra pars compacta and their principal axon projections to the striatum. Degeneration of the nigrostriatal tract is considered the hallmark lesion of the disease; however, several other extranigral sites exhibit pathology: the locus coeruleus and subcoeruleus complex, reticular formation and raphe nuclei, dorsal nuclei of the Vagus, and nucleus basalis of Meynert may all display cell loss.¹⁵ Aptly named for its dark appearance in the adult human brain, the substantia nigra pars compacta consists mainly of dopamine neurons that contain the pigment neuromelanin, a product of catecholamine metabolism, which is visibly reduced in intensity in the postmortem PD brain. Dopamine neuron loss does not occur uniformly throughout the substantia nigra, and the pattern of neuron death is distinct to the disease, differing from the typical loss of dopamine neurons associated with aging alone, which occurs predominantly in the dorsal tier of the substantia nigra.¹⁶ Neurons of the nigrostriatal tract exhibit dieback, with the degenerative process beginning at the nerve terminal and extending retrogradely to the cell body with medioventral loss of the nigral regions showing more early lesions of PD and extending laterally.¹⁷ The distinctive pattern of loss suggests that dopamine neuron death in PD is not merely due to mechanisms of accelerated aging.

The other key pathological feature of PD is the cellular accumulation of Lewy bodies (LBs) and Lewy neurites (LNs), which are protein accumulations within the somal cytoplasm of neurons (LBs) and their processes (LNs), in the substantia nigra and other regions.¹⁸ Lewy bodies and neurites consist predominantly of aggregated α-synuclein protein with a variety of post-translational modifications, including phosphorylation, ubiquitination, nitration, and oxidation of several residues.¹⁹

The role of α-synuclein in the healthy brain remains somewhat unclear, though there is evidence that it participates in synaptic vesicle function.^15,20,21 α-Synuclein point mutations, (wildtype) gene duplications and triplications, and polymorphisms that increase expression of wildtype α-synuclein all cause PD.^22–25 This genetic information, together with the fact that α-synuclein accumulates in Lewy pathology even in idiopathic PD, suggests the central importance of this protein in almost all cases of the disease.²⁶ Neuropathological staging of PD progression is assessed by immunostaining of accumulated α-synuclein, beginning in the caudal brainstem (or olfactory bulb) and spreading rostrally to the neocortex over the course of the disease.¹⁸ According to this scheme, classical involvement of the nigrostriatal neurons occurs in the middle stages of the disease. It is currently unclear whether the spread of α-synuclein pathology represents prion-like cell-to-cell transfer of the protein (discussed below) or simply reflects the relative vulnerabilities of various neuronal populations over the long course of the disease.

α-Synuclein accumulation and aggregation and neuronal death are accompanied by a glial-driven neuroinflammatory response.²⁷ The involvement of glial cells in PD pathogenesis is proposed as both a beneficial response in an attempt to preserve damaged neurons, as well as a source of unregulated inflammation that can drive further neuronal damage.^14,28,29 What remains less obvious is whether neuroinflammation might sometimes be an inciting factor in PD, or merely a response to mitigate the damage that has already occurred in neurons.

The resident CNS macrophage cells, microglia, are the key enforcers of the immune response in the brain, regulating inflammatory protein expression and recruiting additional immunological participants, including t-lymphocytes, from the periphery.^30,31 It is also widely recognized that astrocytes, the most abundant cell type in the brain, are essential to the inflammatory response associated with progressive dopamine neuron loss in the substantia nigra.^32,33 Postmortem examination of microglia and astrocytes reveals an activated, hypertrophic cell phenotype within brains of individuals with PD, appearing most intensely in the ventra...