Preface

Parkinson’s disease (PD) was first described in detail in 1817 by the London surgeon James Parkinson, who referred to the disorder as ‘paralysis agitans’ or ‘shaking palsy’. PD is now defined as a chronic and progressive neurodegenerative disorder that currently affects ∼1 million individuals in the US alone, and ∼10 million around the world. Importantly, from 2006 to 2016 the population affected with PD doubled, while only a 10% increase in the US population was reported. The exact prevalence of PD is unclear as the disease is only diagnosed after the pathogenic process is far advanced. Thus, the exact number of individuals with PD is expected to be higher than the actual number of cases diagnosed. Economically, the estimated cost of PD in the US is ∼$25 million per year in both treatment and lost income from the inability to work.

PD prevalence and incidence increase exponentially for individuals 65 to 85 years of age. While aging is considered the major risk factor for PD, the etiology of the disease is still largely unclear. Around 10% of diagnosed cases have been linked to inherited (familial) mutations in genes encoding proteins such as α-synuclein, Parkin, PINK1, DJ-1, and LRRK2, while other genetic modifications only increase the risk of developing the disease. The remaining ∼90% of PD cases are sporadic, of which ∼5% are linked to de novo mutations primarily in the α-synuclein and LRRK2 genes. For those sporadic cases without a clear delineated genetic background (∼85% of total PD cases), it is hypothesized that environmental or occupational exposures are important contributors to neuronal cell loss. Thus, it is now considered that aging, genetics and environmental/occupational risk factors contribute to PD.

The primary clinical phenotype of PD is what is called parkinsonism, a movement disorder that is characterized by tremor at rest, bradykinesia, rigidity and postural instability, which is directly associated with the depletion of dopamine neurotransmission from degenerated dopaminergic A9 neurons in the substantia nigra pars compacta (SNpc) innervating the striatum. Neuronal degeneration in PD affects other areas of the brain as the disease progresses, but SNpc dopaminergic neurons have been considered one of the primary and likely more sensitive targeted neuronal populations in PD. Importantly, pathological features in the olfactory bulb and brain stem that correlate with early nonmotor dysfunction in the sense of smell and sleep regulation, as well as the degeneration of dopaminergic neurons in the intestine leading to gastrointestinal dysfunction, are considered important components of the disease. To date, the bulk of research in the PD field has been focused on understanding the mechanisms behind the loss of SNpc dopaminergic neurons, but what makes these cells a primary pathological target in PD, and what makes them particularly sensitive to PD risk factors, remains unclear.

Since the late 1970s and early 1980s, oxidative stress has been recognized as a biomarker of the imbalance in redox homeostasis that occurs during the progressive loss of dopaminergic neurons in the brains of PD patients. Byproducts of protein, lipid and nucleic acid oxidation are found in post-mortem PD brain samples. It has been established that mitochondrial dysfunction, inflammatory processes, the pro-oxidant metabolism of dopamine, and metal-catalyzed free-radical formation combine to generate oxidative damage in dopaminergic neurons. Importantly, recent evidence has demonstrated that aside from non-specific oxidative damage, alterations in redox homeostasis associated with PD result in perturbations of enzymatic and signalling processes that are essential for neuronal physiology. Examples of these perturbations include (i) alterations in protein quality control mechanisms that lead to the accumulation of protein inclusions of α-synuclein (Lewy bodies); and (ii) energy failure that renders nigral dopaminergic neurons (which have high energy demands because of their extensive arborization and active pacemaking activity) very sensitive to ATP depletion.

This book aims to highlight recent advances regarding the role of alterations in redox homeostasis in PD pathogenesis. A complete overview of themes including mitochondrial dysfunction, iron and dopamine metabolism, antioxidants, protein aggregation/oxidation and others is reviewed. From this work emerges a strong sense of the rapid pace of discovery in the PD field, but also of substantial knowledge gaps that must be addressed if we are to meet the over-arching goals of identifying biomarkers for earlier diagnosis and developing disease-altering therapies.

Rodrigo Franco

University of Nebraska-Lincoln, NE, USA

Jonathan Doorn

The University of Iowa, IA, USA

Jean-Christophe Rochet

Purdue University, IN, USA