The Molecular and Cellular Basis of Neurodegenerative Diseases

Underlying Mechanisms

Michael S. Wolfe

• Publisher: Academic Press
• Year: 2018
• ISBN:
  9780128113059
• Topic: Biological Sciences
• Subtopic: Neuroscience
• Index: Biological Sciences

The Molecular and Cellular Basis of Neurodegenerative Diseases: Underlying Mechanisms presents the pathology, genetics, biochemistry and cell biology of the major human neurodegenerative diseases, including Alzheimer's, Parkinson's, frontotemporal dementia, ALS, Huntington's, and prion diseases. Edited and authored by internationally recognized leaders in the field, the book's chapters explore their pathogenic commonalities and differences, also including discussions of animal models and prospects for therapeutics. Diseases are presented first, with common mechanisms later. Individual chapters discuss each major neurodegenerative disease, integrating this information to offer multiple molecular and cellular mechanisms that diseases may have in common.

This book provides readers with a timely update on this rapidly advancing area of investigation, presenting an invaluable resource for researchers in the field.

• Covers the spectrum of neurodegenerative diseases and their complex genetic, pathological, biochemical and cellular features
• Focuses on leading hypotheses regarding the biochemical and cellular dysfunctions that cause neurodegeneration
• Details features, advantages and limitations of animal models, as well as prospects for therapeutic development
• Authored by internationally recognized leaders in the field
• Includes illustrations that help clarify and consolidate complex concepts

Chapter 1

Solving the Puzzle of Neurodegeneration

Michael S. Wolfe, University of Kansas, Lawrence, KS, United States

Abstract

Neurodegenerative disease is a major health problem worldwide. While no effective therapeutics have been developed to slow, halt or prevent any neurodegenerative disease, considerable progress has been made toward identifying pathological biomolecules and mutations associated with familial disease. These findings have stimulated the exploration of hypotheses about the molecular and cellular processes that lead to neurodegeneration. Common themes include protein misfolding and aggregation, insufficient protein clearance, dysfunctional mitochondria and altered energy metabolism, disrupted axonal transport, neuroinflammation, and RNA-mediated toxicity. The transsynaptic spread of pathological protein seeds from neuron to neuron is also emerging as an important common theme with implications for developing therapeutics. Aging is a general risk factor for neurodegenerative diseases, as postmitotic neurons and their unique morphology and function make them especially vulnerable to disrupted cellular homeostasis that occurs with age. A wide variety of animal models have been developed, particular transgenic mice, which provide critical tools to test hypotheses about pathogenic mechanisms and candidate therapeutics. Advances in diagnostics are essential for identifying presymptomatic at-risk individuals and testing agents for prevention, as considerable neurodegeneration has already occurred by the time of disease onset. The prospects for discovering effective therapeutics for these devastating diseases are promising but will require filling in gaps in knowledge, examining assumptions regarding disease mechanisms, and a committing to the exploration of a variety of targets.

Keywords

Molecular pathology; mutations; pathogenic mechanism; animal models; therapeutics

Outline

• Introduction: The General Problem of Neurodegeneration 1
• Epidemiology and Clinical Presentation 3
• Molecular Pathology 5
• Genetics 6
• Molecular Clues to Mechanisms of Pathogenesis 8
• Common Themes and Controversies in Neurodegeneration 10
• Animal Models 13
• Prospects for Therapeutics 16
• Conclusions and Perspective 17
• References 18

Introduction: The General Problem of Neurodegeneration

Neurodegenerative diseases are among the most difficult biomedical problems to solve. Despite intense efforts around the world by many laboratories, both academic and industrial, little can be done for the patient who contracts one of these debilitating and deadly disorders, which include Alzheimer’s disease (AD), Parkinson’s disease (PD), frontotemporal dementia (FTD), amyotrophic lateral sclerosis (ALS), Huntington’s disease (HD), and prion diseases.

All approved therapeutics, at best, work at the symptomatic level; none slow or stop the inexorable loss of neurons and neuronal connections. Although tremendous progress has been made toward understanding the molecular and cellular basis of neurodegenerative diseases, this progress has yet to be translated into efficacious medicines. The failure of so many drug candidates in the clinic suggests that our understanding of disease mechanisms is still insufficient.

The need to solve these problems is dire. Over six million people in the United States, and perhaps over 50 million worldwide, have a neurodegenerative disease (Alzheimer’s_Association, 2017; Parkinson’s_Disease_Foundation, 2017; World_Alzheimer_Report, 2015). These diseases are invariably progressive, devastatingly debilitating, and ultimately lethal. As the victim becomes more and more disabled, the strain—emotional, physical, and financial—on patients, their families, and caregivers can become overwhelming. The healthcare costs become exorbitant, and as age is generally the greatest risk factor for acquiring a neurodegenerative disorder, demographic changes suggest societies will be overburdened in the decades to come.

A major part of the reason why neurodegenerative diseases have been so difficult to solve therapeutically is the special characteristics of neurons, which are postmitotic and generally not replaced once lost. Although neurogenesis does occur to a limited extent in the adult human brain (Bergmann, Spalding, & Frisen, 2015), the great majority of the approximately 100 billion neurons are in place around the time of birth (Johnson, 2001). Furthermore, neurons can be especially vulnerable to disease because their axons can extend large distances to connect with other neurons. Some, for example those of certain motor neurons, may extend a meter or more. Axons, as well as dendrites, require transport systems to convey needed biomolecules and organelles to distance synapses. The disruption and blocking of these systems can lead to synaptic failure, and the health of neurons depends on healthy synaptic connections (Morfini et al., 2009). Synaptic failure can lead to neuronal loss.

These characteristics—postmitotic, largely irreplaceable, long processes, and dependence on proper connections—make neurons particular vulnerable. There are many ways to kill neurons. One route is proteotoxicity, the buildup of toxic proteins due to overproduction, or inefficient clearance (Douglas & Dillin, 2010). In most neurodegenerative diseases, abnormal deposition of specific proteins in the brain is a defining feature (Table 1.1). The classic pathological description of AD is the deposition of the amyloid β-protein in extracellular plaques and the intracellular accumulation of neurofibrillary tangles formed by the protein tau (Vinters, 2015). Other diseases such as FTD are classified as tauopathies, with tau deposition similar to that seen in AD but without amyloid plaques (Lee, Goedert, & Trojanowski, 2001; Wang & Mandelkow, 2016). In PD, the membrane-associated protein α-synuclein aggregates within dopaminergic neurons of the substantia nigra (Kalia & Lang, 2015). ALS commonly displays deposition of the TAR DNA-binding protein 43 (TDP-43) in motor neurons (Neumann, 2009), and the huntingtin (Htt) protein can be found aggregated in neurons of the basal ganglia in HD (Walker, 2007). Prion diseases, such as Creutzfeldt–Jakob disease (CJD), display plaques composed of the prion protein (PrP) (Johnson, 2005).

Table 1.1

Primary Familial Genes and Molecular Pathology for Major Neurodegenerative Diseases

Neurodegenerative Disease	Mutant Genes	Protein Deposition
Alzheimer’s disease	APP, presenilins	Aβ, tau
Frontotemporal dementia	Tau, progranulin, c9orf72	Tau, TDP-43
Amyotrophic lateral sclerosis	TDP-43, c9orf72	TDP-43
Parkinson’s disease	α-Synuclein, LRRK2	α-Synuclein
Huntington’s disease	Huntingtin	Huntingtin
Prion diseases	PrP	PrP

The pathways to protein aggregation include overproduction of the disease-associated protein in rare genetic cases. Typically though, these proteins become misfolded, due to the failure of molecular chaperones to ensure proper protein folding. As a result, they are not cleared sufficiently, due to the inability of the ubiquitin-proteasome system or autophagic mechanisms to keep up (Yerbury et al., 2016). Other mechanisms by which neurons become dysfunctional or are destroyed involve RNA toxicity, in which mRNA may become enmeshed in RNA foci or specific mRNA aggregates, causing gain of neurotoxic function as well as loss of normal function (Wojciechowska & Krzyzosiak, 2011). Neuroinflammation provides yet more routes to neurotoxicity, through noncell autonomous effects of support cells such as astrocytes, or of the brain’s immune cells, microglia (Ransohoff, 2016).

Why certain types of neurons or neuronal networks are particularly vulnerable to the abnormal buildup of certain proteins and RNA is unclear and remains a central problem in this field of investigation. What is clear is that this selective neurotoxicity leads to the manifestation of a specific disease. For instance, because neurons of the substantia nigra are unable to effectively clear misfolded or aggregated α-synuclein and are selectively vulnerable to this protein, the result is PD, as these neurons are important in controlling movement. Selective vulnerability of neurons to abnormal tau aggregates in the frontotemporal lobe lead to the specific cognitive and behavioral symptoms in FTD. Deciphering why specific neurons and neuronal networks are affected by certain molecular changes would help elucidate why these molecular changes cause-specific neurodegenerative diseases.

The hope is that elucidating the molecular and cellular basis of neurodegenerative diseases will reveal new therapeutic targets, provide critical information about how an ideal drug should interact with and affect its target, and suggest screening strategies for drug discovery. What follows is a general overview of the nature of these diseases, current hypotheses and evidence for disease mechanisms, important remaining questions, and potential avenues for solving these complex puzzles and developing effective therapeutics.

Epidemiology and Clinical Presentation

AD is the most common neurodegenerative disorder, affecting nearly six million people in the United States and over 35 million worldwide (Prince et al., 2013). The illness manifests itself primarily as a decline in memory and cognition, a consequence of degeneration of the hippocampus and the neocortex, and generally strikes those over age 65, although some 1%–2% of cases are early-onset genetic forms of the disease (Alves, Correia, Miguel, Alegria, & Bugalho, 2012). On average, the course of the disease is roughly 8 years from the onset of symptoms until death, although this can be as long as 20 years. The debilitating nature of the disease, combined with the slow decline and large numbers of people affected, make AD highly costly to society.

FTD is an umbrella term for a spectrum of related diseases that range from decline in language ability to movement disorders to dramatic personality changes and compulsive behaviors (Seelaar, Rohrer, Pijnenburg, Fox, & van Swieten, 2011). As the name suggests, the degeneration takes place primarily in the frontal and temporal lobes. Although not well appreciated by the public, FTD is the most common form of dementia in those under 65 years of age, typically between ages 45 and 64. At least 15% of cases are familial, following a Mendelian genetic pattern of inheritance, and a genetic cause may account for up to 40% of all cases of FTD.

PD is the most common neurodegenerative movement disorder, striking 1% of all people over the age of 65 (Sveinbjornsdottir, 2016). The disease manifests itself clinically with symptoms that include a resting tremor in the limbs and face, bradykinesia (slowness of movement), rigidity in the limbs and trunk, and postural instability. These symptoms are due to the destruction of neurons in the pars compacta of the substantia nigra in the midbrain, neurons that are integrated in circuits that control areas of the basal ganglia involved in voluntary movement. The neurons that are lost are dopaminergic, so treatment with the dopamine precursor L-DOPA has been a long-standing treatment of symptoms. However, this replacement therapy does not stop the underlying neurodegenerative process and ultimately becomes ineffective. Survival after diagnosis of PD is generally between 7 and 11 years (de Lau, Schipper, Hofman, Koudstaal, & Breteler, 2005).

ALS involves the progressive degeneration of motor neurons in the brain and spinal cord (Taylor, Brown, & Cleveland, 2016). The resulting reduced innervation of muscles leads to their wasting (thus “amyotrophic”) and descending axons in the lateral spinal cord appear scarred (thus “lateral sclerosis”). ALS is a relatively rare disease, with some 20,000–30,000 in the United States affected at a given time. The disease progression is generally very rapid, with death typically coming 3–5 years after diagnosis, although some cases can very slowly progress over decades. The disease typically strikes in middle adulthood, with a mean age of onset of 55 years, with initial symptoms of subtle cramping or weakness in muscles of the limbs or those involved in speech and swallowing. Ultimately, the disease progresses to paralysis of most skeletal muscles.

HD is the only major neurodegenerative disease that is 100% hereditary (Walker, 2007). HD clinically presents with symptoms overlapping with those of AD, PD, and ALS. The disease is commonly considered a movement disorder, with its original name being Huntington’s chorea, as involuntary movement of the limbs was thought to resembl...

Table of contents

• Cover image
• Title page
• Table of Contents
• Copyright
• Dedication
• List of Contributors
• Preface
• Chapter 1. Solving the Puzzle of Neurodegeneration
• Chapter 2. Prion Diseases
• Chapter 3. Alzheimer’s Disease: Toward a Quantitative Biological Approach in Describing its Natural History and Underlying Mechanisms
• Chapter 4. Neurodegeneration and the Ordered Assembly of Tau
• Chapter 5. Amyotrophic Lateral Sclerosis and Other TDP-43 Proteinopathies
• Chapter 6. Parkinson’s Disease and Other Synucleinopathies
• Chapter 7. Huntington’s Disease and Other Polyglutamine Repeat Diseases: Molecular Mechanisms and Pathogenic Pathways
• Chapter 8. Prion-Like Propagation in Neurodegenerative Diseases
• Chapter 9. Neurodegenerative Diseases as Protein Folding Disorders
• Chapter 10. Heat Shock Proteins and Protein Quality Control in Alzheimer’s Disease
• Chapter 11. Neurodegenerative Diseases and Autophagy
• Chapter 12. Neurodegenerative Diseases and Axonal Transport
• Chapter 13. Mitochondrial Function and Neurodegenerative Diseases
• Chapter 14. Non-cell Autonomous Degeneration: Role of Astrocytes in Neurodegenerative Diseases
• Chapter 15. Neurodegenerative Diseases and RNA-Mediated Toxicity
• Chapter 16. Neuroinflammation in Age-Related Neurodegenerative Diseases
• Chapter 17. Neurodegenerative Diseases and the Aging Brain
• Index