Genetics, Neurology, Behavior, and Diet in Parkinson's Disease

The Neuroscience of Parkinson's Disease, Volume 2

Colin R Martin, Victor R Preedy, Colin R. Martin, Victor R. Preedy

• Publisher: Academic Press
• Year: 2020
• Print ISBN:
  9780128159507
• eBook ISBN:
  9780128159514
• Topic: Ciencias biológicas
• Subtopic: Fisiología

Genetics, Neurology, Behavior, and Diet in Parkinson's Disease: The Neuroscience of Parkinson's Disease, Volume 2 provides a single source of material covering different scientific domains of neuropathology underlying this condition. The book covers a wide range of subjects and unravels the complex relationships between genetics, molecular biology, pharmaceutical chemistry, neurobiology, imaging, assessments, and treatment regimens. It fills a much-needed gap as a "one-stop" synopsis of everything to do with the neurology and neuroscience related to Parkinson's disease—from chemicals and cells to individuals. It is an invaluable resource for neuroscientists, neurologists, and anyone in the field. - Offers the most comprehensive coverage of a broad range of topics related to Parkinson's disease - Serves as a foundational collection for neuroscientists and neurologists on the biology of disease and brain dysfunction - Contains in each chapter an abstract, key facts, mini dictionary of terms, and summary points to aid in understanding - Features preclinical and clinical studies to help researchers map out key areas for research and further clinical recommendations - Serves as a "one-stop" source for everything you need to know about Parkinson's disease

Part I

Genetics, molecular and cellular biology

Outline

Chapter 1. Leucine-rich repeat kinase 2 (LRRK2) and Parkinson’s disease: from genetics to pathobiology

Chapter 2. Alpha-synuclein gene and Parkinson’s disease

Chapter 3. The DJ-1 gene and protein: links with Parkinson’s disease

Chapter 4. Regulation of tyrosine hydroxylase: relevance to Parkinson’s disease

Chapter 5. Linking glucocerebrosidase gene (GBA) variants and Parkinson’s disease

Chapter 6. Astrocytes and microglia in Parkinson’s disease and animal models

Chapter 7. The role of autophagy in Parkinson’s disease etiopathogenesis

Chapter 8. The mitochondrial network in Parkinson’s disease

Chapter 9. Signal transduction in Parkinson’s disease: modulation of neurotransmission, symptomatology, and therapy

Chapter 10. Oxidative stress signaling and regulated cell death in Parkinson’s disease

Chapter 11. Subcellular-specific alpha-synuclein in Parkinson’s disease

Chapter 12. Melanocortin 1 receptor: Parkinson’s disease, melanoma risk, and neuroprotection

Chapter 13. Energy regulation and Parkinson’s disease

Chapter 14. Linking rotigotine, Parkinson’s disease, and brain-derived neurotrophic factor

Chapter 1: Leucine-rich repeat kinase 2 (LRRK2) and Parkinson's disease: from genetics to pathobiology

Susanna Cogo, and Elisa Greggio Department of Biology, University of Padova, Padova, Italy

Abstract

Point mutations in the leucine-rich repeat kinase 2 (LRRK2) gene cause autosomal-dominant inherited Parkinson's disease (PD), and more common variations increase lifetime risk for PD. LRRK2 encodes a multidomain enzyme with kinase and GTPase activities. Because the hyperactive G2019S mutation in the kinase domain represents a common genetic cause of PD, LRRK2 is currently the most attractive pharmacological target in PD owing to its “druggable” nature, with more than 100 inhibitors developed to date. However, if LRRK2 inhibitors have entered phase I clinical trials, the current understanding of LRRK2 function and dysfunction in neuronal and nonneuronal cells is still primitive. This chapter offers a comprehensive overview of LRRK2 genetics, biochemistry, and biology, as well as a therapeutic perspective of targeting LRRK2 as a disease-modifying therapy in PD.

Keywords

Autophagy; Cytoskeleton; GTPase; Inflammation; Inhibitors; Kinase; LRRK2; Microglia; Neuron; Phosphorylation; Synapse

List of abbreviations

AMP Adenosine monophosphate

CD Crohn's disease

CK1α Casein kinase 1α

COR C-Terminal of ROC

GTP Guanosine triphosphate

GWAS Genome-wide association studies

LRRK2 Leucine-rich repeat kinase 2

PD Parkinson's disease

ROC Ras of complex proteins

SPNs Spiny projecting neurons

Minidictionary of terms

Autophagy Evolutionary conserved process fundamental for cellular homeostasis, consisting of the delivery of intracellular macromolecules and organelles (either self or foreign) to the lysosome for degradation and recycling.

GTPase activity Enzymatic activity that converts one molecule of guanosine triphosphate (GTP) into one of guanosine diphosphate (GDP), a process that allows the activation of a cellular effector binding the GTPase in its GTP-bound state.

Inflammation A local response to an infection, irritation, or injury that produces redness, heat, pain, and swelling and is accompanied by leukocytic infiltration to eliminate the noxious agent.

Kinase activity Enzymatic activity that permits the transfer of a phosphate group from a high-energy donating molecule (adenosine triphosphate, ATP) to a substrate as a signal for regulation.

Synapse The point at which a nervous impulse (either electrical or chemical) passes from a neuron to another.

Introduction

Among all the genetic contributors of Parkinson's disease (PD), mutations in the leucine-rich repeat kinase 2 (LRRK2) gene, encoding a complex GTPase-kinase, represent the single most common cause of disease (Paisán-Ruiz, Lewis, & Singleton, 2013). LRRK2 belongs to the family of ROCO proteins, characterized by the presence of the bidomain Ras of complex proteins (ROC) and C-terminal of ROC (COR). LRRK2 also possesses a serine-threonine kinase domain and multiple protein-to-protein interaction domains, which suggests both signaling and scaffolding roles during signal transduction. LRRK2 is expressed in multiple tissues and organs, with moderate to high expression in the brain, lungs, kidneys, and circulating immune cells (Biskup et al., 2007) (Fig. 1.1). Within the brain, LRRK2 is found in neuronal and glial cells, with high expression in the striatum, which receives the dopaminergic projecting fibers from the substantia nigra pars compacta (West et al., 2014). In terms of function, LRRK2 has been linked to multiple cellular processes, including autophagy and endo-lysosomal pathways, cytoskeletal dynamics, and synaptic vesicle trafficking (Fig. 1.2), although the detailed molecular mechanisms are not fully understood. This chapter will provide a detailed overview of LRRK2 genetics, biochemistry, and biology, and will discuss the therapeutic potential of targeting LRRK2 in PD.

Figure 1.1 Leucine-rich repeat kinase 2 (LRRK2) expression in different tissues. LRRK2 is expressed in most body tissues, but its highest expression is in the lungs, kidneys, and peripheral blood mononuclear cells (PBMCs).

Leucine-rich repeat kinase 2 genetics

In 2002, Funayama and collaborators identified a large Japanese kindred, known as the Sagamihara family, from the Japanese region from which the family originated, with an autosomal-dominant form of PD. This novel PD locus, termed PARK8, was mapped on chromosome 12 (Funayama et al., 2002). In 2004, two groups subsequently reported that the underlying genetic cause of PARK8-associated PD was the...

Table of contents

• Cover image
• Title page
• Table of Contents
• Copyright
• Dedication
• Contributors
• Foreword
• Preface
• Part I. Genetics, molecular and cellular biology
• Part II. Neurology, physiology and imaging
• Part III. Behaviour and psychopathology
• Part IV. Diet and nutrition
• Part V:. Models, modelling and resources
• Chapter 45. Neuroscience of Parkinson's disease: recommended reading and resources
• Index