The Molecular and Cellular Basis of Neurodegenerative

Diseases Underlying Mechanisms

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 List of Contributors

Stephen P. Andrews Alzheimer’s Research UK Audrey S. Dickey Duke University School of

Cambridge Drug Discovery Institute, University Medicine, Durham, NC, United States
of Cambridge, Cambridge, United Kingdom Chad A. Dickey University of South Florida,
Avraham Ashkenazi Cambridge Institute for Tampa, FL, United States
Medical Research, University of Cambridge, Cheng Fang Boston University School of Medicine,
Cambridge Biomedical Campus, Cambridge, Boston, MA, United States
United Kingdom
Angeleen Fleming Cambridge Institute for
Veerle Baekelandt KU Leuven, Leuven, Belgium Medical Research, University of Cambridge,
Jeremy D. Baker University of South Florida, Cambridge Biomedical Campus, Cambridge,
Tampa, FL, United States United Kingdom
Konrad Beyreuther The University of Heidelberg, Jens Füllgrabe Cambridge Institute for Medical
Heidelberg, Germany Research, University of Cambridge, Cambridge
Laura J. Blair University of South Florida, Tampa, Biomedical Campus, Cambridge, United Kingdom
FL, United States Stephen K. Godin Massachusetts Institute of
Azad Bonni Department of Neuroscience, Technology, Cambridge, MA, United States
Washington University School of Medicine, St. Michel Goedert MRC Laboratory of Molecular
Louis, MO, United States Biology, Cambridge, United Kingdom
Erin Bove-Fenderson Boston University School of Lawrence S. Goldstein University of California
Medicine, Boston, MA, United States San Diego, School of Medicine, San Diego, CA,
Patrik Brundin Van Andel Research Institute, United States
Grand Rapids, MI, United States Jorge Gomez-Deza King’s College London,
Andrea Caricasole Alzheimer’s Research UK London, United Kingdom
Cambridge Drug Discovery Institute, University Ben Gu The Florey Institute, The University of
of Cambridge, Cambridge, United Kingdom Melbourne, Melbourne, VIC, Australia
Amarallys F. Cintron Emory University School of David A. Harris Boston University School of
Medicine, Atlanta, GA, United States Medicine, Boston, MA, United States
Mark R. Cookson National Institute on Aging, Harm H. Kampinga University of Groningen,
National Institutes of Health, Bethesda, MD, Groningen, The Netherlands
United States Scott Koppel University of Kansas School of
Utpal Das University of California San Diego, Medicine, Kansas City, KS, United States
School of Medicine, San Diego, CA, United States John Koren III University of South Florida,
Sarah M. de Jager Cambridge Institute for Medical Tampa, FL, United States
Research, University of Cambridge, Cambridge Albert R. La Spada Duke University School of
Biomedical Campus, Cambridge, United Kingdom Medicine, Durham, NC, United States
Maria E. de Sousa Rodrigues Emory University Simon Laws Edith Cowan University, Joondalup,
School of Medicine, Atlanta, GA, United States WA, Australia

xi
xii LIST OF CONTRIBUTORS

Floriana Licitra Cambridge Institute for Medical Lindsey B. Shelton University of South Florida,
Research, University of Cambridge, Cambridge Tampa, FL, United States
Biomedical Campus, Cambridge, United Kingdom John Skidmore Alzheimer’s Research UK
Yen Y. Lim The Florey Institute, The University of Cambridge Drug Discovery Institute, University
Melbourne, Melbourne, VIC, Australia of Cambridge, Cambridge, United Kingdom
Ana Lopez Cambridge Institute for Medical Sarah E. Smith Medical Scientist Training
Research, University of Cambridge, Cambridge Program, Washington University School of
Biomedical Campus, Cambridge, United Kingdom Medicine, St. Louis, MO, United States
Kathryn P. MacPherson Emory University School Russell H. Swerdlow University of Kansas
of Medicine, Atlanta, GA, United States School of Medicine, Kansas City, KS, United
Colin L. Masters The Florey Institute, The States
University of Melbourne, Melbourne, VIC, Australia Malú G. Tansey Emory University School of
Alex J. McDonald Boston University School of Medicine, Atlanta, GA, United States
Medicine, Boston, MA, United States Tiffany W. Todd Mayo Clinic, Jacksonville, FL,
Robert C.C. Mercer Boston University School of United States
Medicine, Boston, MA, United States Li-Huei Tsai Massachusetts Institute of
Mariana Pavel Cambridge Institute for Medical Technology, Cambridge, MA, United States
Research, University of Cambridge, Cambridge Vladimir N. Uversky University of South Florida,
Biomedical Campus, Cambridge, United Kingdom Tampa, FL, United States
Wouter Peelaerts KU Leuven, Leuven, Belgium; Fred W. van Leeuwen University of Maastricht,
Van Andel Research Institute, Grand Rapids, MI, Maastricht, The Netherlands
United States Mariella Vicinanza Cambridge Institute for
Leonard Petrucelli Mayo Clinic, Jacksonville, FL, Medical Research, University of Cambridge,
United States Cambridge Biomedical Campus, Cambridge,
Claudia Puri Cambridge Institute for Medical United Kingdom
Research, University of Cambridge, Cambridge Victor L. Villemagne The Florey Institute, The
Biomedical Campus, Cambridge, United Kingdom University of Melbourne, Melbourne, VIC,
Maurizio Renna Cambridge Institute for Medical Australia; Austin Health, Melbourne, VIC,
Research, University of Cambridge, Cambridge Australia
Biomedical Campus, Cambridge, United Kingdom Alex von Schulze University of Kansas School of
Thomas Ricketts Cambridge Institute for Medical Medicine, Kansas City, KS, United States
Research, University of Cambridge, Cambridge Xiaowan Wang University of Kansas School of
Biomedical Campus, Cambridge, United Kingdom Medicine, Kansas City, KS, United States
Blaine Roberts The Florey Institute, The University Jack M. Webster University of South Florida,
of Melbourne, Melbourne, VIC, Australia Tampa, FL, United States
David C. Rubinsztein Cambridge Institute for Ian Weidling University of Kansas School of
Medical Research, University of Cambridge, Medicine, Kansas City, KS, United States
Cambridge Biomedical Campus, Cambridge, Heather M. Wilkins University of Kansas School
United Kingdom; UK Dementia Research of Medicine, Kansas City, KS, United States
Institute, Cambridge Biomedical Campus,
Michael S. Wolfe University of Kansas, Lawrence,
Cambridge, United Kingdom
KS, United States
Jinsoo Seo Massachusetts Institute of Technology,
Bei Wu Boston University School of Medicine,
Cambridge, MA, United States
Boston, MA, United States
Christopher E. Shaw King’s College London,
London, United Kingdom
 Preface

Neurodegenerative diseases are among the their epidemiology, genetics, pathology, and
most devastating of human ailments, slowly molecular and cell biology, as well as animal
robbing a person of memories, reason, person- models and the special challenges to develop-
ality, or movement. All are ultimately fatal. ing therapeutics. The next set of chapters
The human cost goes far beyond the patient, as focuses on particular neurodegenerative dis-
family and friends watch their loved one dete- eases, beginning with prion diseases, as recent
riorate and caregivers struggle to provide daily research suggests that many neurodegenera-
assistance in the face of relentless decline. tive diseases may involve similar mechanisms
Economic costs are exorbitant as well, not only for the spread of molecular pathology. Specific
because of medical expenses but also lost pro- chapters follow on Alzheimer’s disease, tauo-
ductivity and wages. pathies such as frontotemporal dementia,
Despite the dire need, there are no medica- amyotrophic lateral sclerosis, Parkinson’s dis-
tions or procedures that effectively slow or halt ease, and Huntington’s disease.
the neurodegenerative process. For Parkinson’s Subsequent chapters focus on general
disease, replacement therapy for lost dopamine mechanisms that are apparently shared by
provides effective relief from tremors and other many neurodegenerative diseases. This includes
motor symptoms. However, the loss of dopa- trans-synaptic propagation of prion-like pro-
minergic neurons in the substantia nigra con- teins, problems with protein folding and quality
tinues, and ultimately replacement therapy control, disruption of axonal transport, mito-
becomes ineffective. For Alzheimer’s disease, chondrial dysfunction, RNA-mediated neuro-
acetylcholinesterase inhibitors boost signaling toxicity, neuroinflammation, and aging. As this
at cholinergic synapses, but neurodegeneration list suggests, there are many ways to cause neu-
continues in areas critical to memory and cog- ronal dysfunction and death. This is due to the
nition, such as the hippocampus. special biology of neurons with processes
Solving these difficult problems in human extending often quite far from the cell body that
health will require better understanding of the need to connect functionally with other neurons
molecular and cellular mechanisms that lead to or effector cells.
pathogenesis and progression. In this book, we The general aim of this book is to provide a
put forward the leading ideas and evidence resource that condenses and consolidates the
regarding these mechanisms as well as pro- overwhelming amount of information in the
spects for developing means of prevention and scientific literature. In doing so, we hope to
treatment of neurodegenerative diseases. Each give the researcher as well as the student a
chapter is authored by an international expert sense of the big picture and common themes
on their topic. and to allow the opportunity to make connec-
We begin with an overview chapter for this tions between seemingly disparate areas of
broad area of biomedical investigation, describ- investigation. We also hope to make clear the
ing the major neurodegenerative diseases and open questions that remain and to suggest

xiii
xiv PREFACE

where the field might be heading. Thus the UCLA for his careful reading and critiquing of
broader goal is to stimulate new ideas and my introductory chapter. Finally, I thank
future research that will ultimately lead to Natalie Farra and Kathy Padilla and their col-
effective means of prevention and treatment. leagues at Elsevier for all their help in bringing
I would like to thank all contributing the idea of this book into reality.
authors for devoting considerable time,
thought, and effort in putting together superb
chapters on challenging topics. More broadly, I Michael S. Wolfe
am grateful to all those carrying out research University of Kansas, Lawrence, KS,
to understand these difficult diseases and work United States
toward prevention and treatment. I also thank September, 2017
my friend and colleague David Teplow at
 C H A P T E R

1
Solving the Puzzle of Neurodegeneration
Michael S. Wolfe
University of Kansas, Lawrence, KS, United States

O U T L I N E

Introduction: The General Problem of Common Themes and Controversies in

Neurodegeneration 1 Neurodegeneration 10
Epidemiology and Clinical Presentation 3 Animal Models 13
Molecular Pathology 5 Prospects for Therapeutics 16
Genetics 6 Conclusions and Perspective 17
Molecular Clues to Mechanisms of References 18
Pathogenesis 8

INTRODUCTION: THE GENERAL All approved therapeutics, at best, work at

PROBLEM OF the symptomatic level; none slow or stop the
NEURODEGENERATION inexorable loss of neurons and neuronal con-
nections. Although tremendous progress has
Neurodegenerative diseases are among the been made toward understanding the molecu-
most difficult biomedical problems to solve. lar and cellular basis of neurodegenerative dis-
Despite intense efforts around the world by eases, this progress has yet to be translated
many laboratories, both academic and indus- into efficacious medicines. The failure of so
trial, little can be done for the patient who con- many drug candidates in the clinic suggests
tracts one of these debilitating and deadly that our understanding of disease mechanisms
disorders, which include Alzheimer’s disease is still insufficient.
(AD), Parkinson’s disease (PD), frontotemporal The need to solve these problems is dire. Over
dementia (FTD), amyotrophic lateral sclerosis six million people in the United States, and per-
(ALS), Huntington’s disease (HD), and prion haps over 50 million worldwide, have a neuro-
diseases. degenerative disease (Alzheimer’s_Association,

The Molecular and Cellular Basis of Neurodegenerative Diseases

DOI: https://doi.org/10.1016/B978-0-12-811304-2.00001-8 1 © 2018 Elsevier Inc. All rights reserved.
2 1. SOLVING THE PUZZLE OF NEURODEGENERATION

2017; Parkinson’s_Disease_Foundation, 2017; health of neurons depends on healthy synaptic

World_Alzheimer_Report, 2015). These diseases connections (Morfini et al., 2009). Synaptic fail-
are invariably progressive, devastatingly debili- ure can lead to neuronal loss.
tating, and ultimately lethal. As the victim These characteristics—postmitotic, largely
becomes more and more disabled, the strain— irreplaceable, long processes, and dependence
emotional, physical, and financial—on patients, on proper connections—make neurons particu-
their families, and caregivers can become over- lar vulnerable. There are many ways to kill
whelming. The healthcare costs become exorbi- neurons. One route is proteotoxicity, the
tant, and as age is generally the greatest risk buildup of toxic proteins due to overproduc-
factor for acquiring a neurodegenerative disor- tion, or inefficient clearance (Douglas & Dillin,
der, demographic changes suggest societies will 2010). In most neurodegenerative diseases,
be overburdened in the decades to come. abnormal deposition of specific proteins in the
A major part of the reason why neurodegen- brain is a defining feature (Table 1.1). The clas-
erative diseases have been so difficult to solve sic pathological description of AD is the depo-
therapeutically is the special characteristics of sition of the amyloid β-protein in extracellular
neurons, which are postmitotic and generally plaques and the intracellular accumulation of
not replaced once lost. Although neurogenesis neurofibrillary tangles formed by the protein
does occur to a limited extent in the adult tau (Vinters, 2015). Other diseases such as FTD
human brain (Bergmann, Spalding, & Frisen, are classified as tauopathies, with tau deposi-
2015), the great majority of the approximately tion similar to that seen in AD but without
100 billion neurons are in place around the amyloid plaques (Lee, Goedert, & Trojanowski,
time of birth (Johnson, 2001). Furthermore, 2001; Wang & Mandelkow, 2016). In PD, the
neurons can be especially vulnerable to disease membrane-associated protein α-synuclein
because their axons can extend large distances aggregates within dopaminergic neurons of the
to connect with other neurons. Some, for exam- substantia nigra (Kalia & Lang, 2015). ALS
ple those of certain motor neurons, may extend commonly displays deposition of the TAR
a meter or more. Axons, as well as dendrites, DNA-binding protein 43 (TDP-43) in motor
require transport systems to convey needed neurons (Neumann, 2009), and the huntingtin
biomolecules and organelles to distance synap- (Htt) protein can be found aggregated in neu-
ses. The disruption and blocking of these sys- rons of the basal ganglia in HD (Walker, 2007).
tems can lead to synaptic failure, and the Prion diseases, such as Creutzfeldt Jakob

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 MOLECULAR AND CELLULAR BASIS OF NEURODEGENERATIVE DISEASES

 EPIDEMIOLOGY AND CLINICAL PRESENTATION 3
disease (CJD), display plaques composed of provide critical information about how an ideal
the prion protein (PrP) (Johnson, 2005). drug should interact with and affect its target,
The pathways to protein aggregation include and suggest screening strategies for drug dis-
overproduction of the disease-associated protein covery. What follows is a general overview of
in rare genetic cases. Typically though, these the nature of these diseases, current hypothe-
proteins become misfolded, due to the failure of ses and evidence for disease mechanisms,
molecular chaperones to ensure proper protein important remaining questions, and potential
folding. As a result, they are not cleared suffi- avenues for solving these complex puzzles and
ciently, due to the inability of the ubiquitin- developing effective therapeutics.
proteasome system or autophagic mechanisms
to keep up (Yerbury et al., 2016). Other mechan-
isms by which neurons become dysfunctional or
are destroyed involve RNA toxicity, in which EPIDEMIOLOGY AND CLINICAL
mRNA may become enmeshed in RNA foci or PRESENTATION
specific mRNA aggregates, causing gain of
neurotoxic function as well as loss of normal AD is the most common neurodegenerative
function (Wojciechowska & Krzyzosiak, 2011). disorder, affecting nearly six million people in
Neuroinflammation provides yet more routes to the United States and over 35 million world-
neurotoxicity, through noncell autonomous wide (Prince et al., 2013). The illness manifests
effects of support cells such as astrocytes, or of itself primarily as a decline in memory and
the brain’s immune cells, microglia (Ransohoff, cognition, a consequence of degeneration of
2016). the hippocampus and the neocortex, and gen-
Why certain types of neurons or neuronal erally strikes those over age 65, although some
networks are particularly vulnerable to the 1% 2% of cases are early-onset genetic forms
abnormal buildup of certain proteins and RNA of the disease (Alves, Correia, Miguel, Alegria,
is unclear and remains a central problem in this & Bugalho, 2012). On average, the course of
field of investigation. What is clear is that this the disease is roughly 8 years from the onset of
selective neurotoxicity leads to the manifesta- symptoms until death, although this can be as
tion of a specific disease. For instance, because long as 20 years. The debilitating nature of the
neurons of the substantia nigra are unable to disease, combined with the slow decline and
effectively clear misfolded or aggregated large numbers of people affected, make AD
α-synuclein and are selectively vulnerable to highly costly to society.
this protein, the result is PD, as these neurons FTD is an umbrella term for a spectrum of
are important in controlling movement. related diseases that range from decline in lan-
Selective vulnerability of neurons to abnormal guage ability to movement disorders to dra-
tau aggregates in the frontotemporal lobe lead matic personality changes and compulsive
to the specific cognitive and behavioral symp- behaviors (Seelaar, Rohrer, Pijnenburg, Fox, &
toms in FTD. Deciphering why specific neurons van Swieten, 2011). As the name suggests, the
and neuronal networks are affected by certain degeneration takes place primarily in the fron-
molecular changes would help elucidate why tal and temporal lobes. Although not well
these molecular changes cause-specific neurode- appreciated by the public, FTD is the most
generative diseases. common form of dementia in those under 65
The hope is that elucidating the molecular years of age, typically between ages 45 and 64.
and cellular basis of neurodegenerative dis- At least 15% of cases are familial, following a
eases will reveal new therapeutic targets, Mendelian genetic pattern of inheritance, and a

THE MOLECULAR AND CELLULAR BASIS OF NEURODEGENERATIVE DISEASES

4 1. SOLVING THE PUZZLE OF NEURODEGENERATION

genetic cause may account for up to 40% of all clinically presents with symptoms overlapping
cases of FTD. with those of AD, PD, and ALS. The disease is
PD is the most common neurodegenerative commonly considered a movement disorder,
movement disorder, striking 1% of all people with its original name being Huntington’s cho-
over the age of 65 (Sveinbjornsdottir, 2016). rea, as involuntary movement of the limbs was
The disease manifests itself clinically with thought to resemble a dance. However, other
symptoms that include a resting tremor in the symptoms include diminished speech and diffi-
limbs and face, bradykinesia (slowness of culty swallowing as well as dementia and per-
movement), rigidity in the limbs and trunk, sonality changes such as depression and
and postural instability. These symptoms are irritability. Disease onset is typically in midlife,
due to the destruction of neurons in the pars although it may strike at any age. The course of
compacta of the substantia nigra in the mid- the illness runs 10 20 years and, like all the
brain, neurons that are integrated in circuits progressive neurodegenerative diseases, is ulti-
that control areas of the basal ganglia involved mately fatal. Although neurodegeneration is
in voluntary movement. The neurons that are widespread in the brain, areas affected early
lost are dopaminergic, so treatment with the include a part of the basal ganglia called the
dopamine precursor L-DOPA has been a long- striatum, involved in motor coordination, cogni-
standing treatment of symptoms. However, tion, and reward and motivation. Other areas
this replacement therapy does not stop the affected include the substantia nigra, parts of
underlying neurodegenerative process and the cerebral cortex, and the hippocampus.
ultimately becomes ineffective. Survival after Prion diseases are rare neurodegenerative
diagnosis of PD is generally between 7 and 11 disorders that may present with different
years (de Lau, Schipper, Hofman, Koudstaal, & symptoms and neuropathology but that are all
Breteler, 2005). caused by a protein agent termed a prion.
ALS involves the progressive degeneration Prion disease can occur sporadically or
of motor neurons in the brain and spinal cord through infection, as well as being inherited
(Taylor, Brown, & Cleveland, 2016). The result- (Johnson, 2005). CJD, fatal familial insomnia
ing reduced innervation of muscles leads to (FFI), Gerstmann Straussler Scheinker syn-
their wasting (thus “amyotrophic”) and des- drome (GSS), and kuru are examples of human
cending axons in the lateral spinal cord appear prion diseases. The study of kuru led to the
scarred (thus “lateral sclerosis”). ALS is a rela- discovery of the infectious nature of these
tively rare disease, with some 20,000 30,000 in brain-wasting diseases. The disease was
the United States affected at a given time. The endemic in the Fore ethnic group in the high-
disease progression is generally very rapid, lands of Papua New Guinea and was found to
with death typically coming 3 5 years after be acquired as a result of ritual cannibalism
diagnosis, although some cases can very slowly involving contact with or ingestion of brains of
progress over decades. The disease typically deceased family members. Prion diseases all
strikes in middle adulthood, with a mean age involve a long incubation period and rapid
of onset of 55 years, with initial symptoms of progression after onset. Postmortem analysis
subtle cramping or weakness in muscles of the reveals a spongiform pathology and extensive
limbs or those involved in speech and swal- plaque deposition of the PrP. Prion diseases
lowing. Ultimately, the disease progresses to also are found in cows (bovine spongiform
paralysis of most skeletal muscles. encephalopathy or mad cow disease), sheep
HD is the only major neurodegenerative dis- (scrapie), and deer and elk (chronic wasting
ease that is 100% hereditary (Walker, 2007). HD disease).

THE MOLECULAR AND CELLULAR BASIS OF NEURODEGENERATIVE DISEASES

 MOLECULAR PATHOLOGY 5

MOLECULAR PATHOLOGY deposits are observed (Irwin et al., 2015). In most

of these cases, the deposits are composed of the
The first clues to molecular mechanisms of RNA-binding protein TDP-43. Normally a
these diseases were their postmortem pathologi- nuclear protein, TDP-43 is translocated to the
cal features. As mentioned earlier, AD is charac- cytoplasm and aggregates in neurons in FTD.
terized by plaque deposition and neurofibrillary TDP-43 is also the main component in deposits
tangles (Vinters, 2015). Biochemical analysis within motor neurons found in most cases of
identified the proteins Aβ and tau as the major ALS, and this and other evidence suggests that
components of the plaques and tangles, respec- FTD and ALS may be related diseases on differ-
tively. Aβ deposition appears to be the earliest ent ends of a spectrum of TDP-43 proteinopa-
pathological change, seen up to 25 years before thies (Geser, Lee, & Trojanowski, 2010).
the expected onset of symptoms. In contrast, Neuronal deposits of other proteins such as
tau deposition, although observed later, is more superoxide dismutase 1 (SOD1) or an RNA-
spatially and temporally correlated with the binding protein related to TDP-43 called fused in
loss of neurons. Together these findings suggest sarcoma (FUS) can be found in rare genetic
that aberrant Aβ could be a pathogenic initiator, forms of ALS (Taylor et al., 2016). RNA foci are
while downstream pathological changes in tau also found in many cases of ALS, composed of
may be the more proximal cause of neurode- transcripts of a gene called c9orf72 that contains
generation. Other pathological events include an expansion of a hexanucleotide repeat region
neuroinflammation, which may be causative or (Haeusler, Donnelly, & Rothstein, 2016).
exacerbating factors of neuronal dysfunction Cytoplasmic aggregates and nuclear inclu-
and loss. sions are also found throughout the brain, but
PD is characterized by the presence of Lewy particularly in the basal ganglia, as a major
bodies in neuronal cell bodies and neuronal and common pathological feature of HD
loss in the pars compacta region of the substan- (Labbadia & Morimoto, 2013). The primary
tia nigra (Kalia & Lang, 2015). Lewy bodies are component of these deposits is a mutated form
deposits of the protein α-synuclein, and the of the Htt protein containing an expansion of a
neurons that are lost are primarily dopaminer- polyglutamate region at the N-terminus of the
gic, innervate the basal ganglia, and are critical protein. Because the interactome of Htt is quite
to motor functions. Deposition of Aβ or tau is large, many other proteins become entrapped
typically not seen in PD unless the subject also as well, including those involved in transcrip-
displayed dementia. tion and protein quality control.
In contrast, neurofibrillary tangles com- Prion diseases display extensive plaque
posed of aggregated tau are found in nearly deposition along with a spongiform pathology.
half of all FTD cases (Irwin et al., 2015). The primary component of these plaques is
Interestingly though, Aβ deposition is not. A PrP, which can assume a variety of possible
spectrum of neurodegenerative diseases collec- conformations and glycosylation patterns capa-
tively called tauopathies share this specific ble of aggregation and spreading throughout
pathology (Ballatore, Lee, & Trojanowski, 2007; the brain (Collinge, 2016). These different con-
Wang & Mandelkow, 2016), leading to the idea formations and glycosylation patterns are
that aberrant Aβ in AD is one of a number of thought to lead to different strains of the infec-
means by which neurotoxic tau can be elicited. tious forms of PrP that affect different regions
In some 50% of other FTD cases, however, of the brain, result in different clinical presen-
tau-negative, ubiquitin-positive protein neuronal tations (e.g., CJD, FFI, and GSS), and affect the

THE MOLECULAR AND CELLULAR BASIS OF NEURODEGENERATIVE DISEASES

6 1. SOLVING THE PUZZLE OF NEURODEGENERATION

ability of PrP to infect different species. The combined with pathological and biochemical
ability of a protein alone to transmit disease evidence, strongly points to a role of Aβ in AD
and even encode different infectious strains pathogenesis (Tanzi & Bertram, 2005).
was a paradigm-shifting discovery for which A major risk factor for sporadic, late-onset
Dr. Stanley Prusiner was awarded the Nobel AD is the apolipoprotein E (APOE) gene, which
Prize in 1997. encodes a cholesterol-transporting protein
Perhaps the most intriguing and common (Cuyvers & Sleegers, 2016). The E4 variant of
pathological finding in neurodegeneration in this gene increases risk (3 4-fold for one allele
recent years has been the increasing apprecia- and 12 15-fold for both alleles), while the E2
tion of the spread of molecular pathology from variant decreases risk and the E3 variant is neu-
neuron to neuron, in a networked manner tral. A rare missense mutation in the gene
through what is termed synaptic transmission encoding an immune cell receptor, triggering
(Guo & Lee, 2014). This process has been lik- receptor expressed on myeloid cells 2 (TREM2),
ened to the assembly and spreading of PrP also confers substantial risk of late-onset AD,
pathology. It is critical to point out, however, providing an important clue to possible roles of
that PrP is the only protein known to be infec- neuroinflammation in AD pathogenesis.
tious and that the prion-like character of other The search for genetic causes of dominantly
proteins involved in neurodegenerative dis- inherited FTD led to the discovery of muta-
eases appears to be limited to the molecular tions in the microtubule-associate protein tau
and cellular levels. Nevertheless, prion-like (MAPT) gene (Goedert & Jakes, 2005; Wang &
assembly and synaptic transmission is an Mandelkow, 2016). These are mostly point
important emerging concept in the field with mutations in the coding region that increase
potential therapeutic implications. This issue the tendency of the protein to aggregate, but
will be discussed in further detail later. some are silent or intronic mutations that shift
pre-mRNA splicing toward a set of normal tau
isoforms that are more prone to aggregation.
GENETICS The discovery of tau mutations causing FTD
bolstered a role of tau in AD as well.
Major clues to disease mechanisms have Interestingly, other familial cases of FTD, with-
also come from genetics, particularly from the out tau pathology but with ubiquitin-positive
study of families with classical Mendelian deposits, are caused by loss-of-function muta-
inheritance patterns. For some neurodegenera- tions in the progranulin (PRG) gene, located in
tive diseases, different genes may be mutated the same region of chromosome 17 as the
in different families, which taken together can MAPT gene (Baker et al., 2006; Cruts et al.,
suggest a particular cellular process, pathway, 2006). Another major site of dominantly inher-
or function. For instance, three genes are sites ited mutations leading to FTD is c9orf72,
of autosomal-dominant missense mutations caused by expansion of a hexanucleotide
that lead to familial early-onset AD: the amy- repeat in the promoter of this gene (Haeusler
loid β-protein precursor (APP), presenilin-1 et al., 2016), suggesting a neurotoxic role of the
(PSEN1) and presenilin-2 (PSEN2). APP is the RNA transcript.
precursor to the Aβ peptide that deposits in the The c9orf72 repeat expansion is also associ-
AD brain, and presenilin is the catalytic com- ated with ALS, accounting for 25% of familial
ponent of γ-secretase, one of two proteases cases and 10% of sporadic cases (Haeusler
responsible for producing the Aβ peptide. et al., 2016; Taylor et al., 2016). Thus, like TDP-
Thus, the genetic evidence from familial cases, 43 pathology, the c9orf72 mutations suggest

THE MOLECULAR AND CELLULAR BASIS OF NEURODEGENERATIVE DISEASES

 GENETICS 7
that FTD and ALS are related diseases: muta- familial PD but also for some 1% 2% of all
tions in the same genes can lead to either dis- sporadic cases of PD. LRRK2 is a large multi-
ease or a combination of the two. FTD and ALS domain protein, and how the mutations alter
are apparently on either end of a spectrum of function to cause disease is still unclear.
possible disease states caused by common Recessive mutations in the DJ-1 gene, encoding
molecular changes (Geser et al., 2010). a protein thought to be important to protect
Missense mutations in SOD1 are responsible neurons from oxidative stress, are also associ-
for another 20% of familial ALS, and these ated with familial PD.
mutations lead to misfolding and aggregation HD is the only major neurodegenerative dis-
of the SOD1 protein. Other mutations associ- ease that is 100% genetic—every case is due to
ated with familial ALS include TARDBP expansion of a CAG trinucleotide repeat in exon
(encoding TDP-43 itself) and FUS, encoding a 1 of the Htt gene that leads to polyglutamate
related RNA-binding protein, suggesting dis- expansion in the encoded protein (Labbadia &
rupted RNA metabolism as a common mecha- Morimoto, 2013). Normally, the number of
nism. Genes encoding proteins involved in repeats range from 16 to 20, and expansion
autophagy such as optineurin, ubiquilin-2, and beyond 35 repeats leads to HD. Htt is a high-
sequestosome-1 are also mutated in familial molecular-weight protein with a large interac-
ALS, pointing to problems with aberrant dis- tome. Polyglutamine expansion occurs in other
posal of cellular waste. Other ALS-causing genes associated with other neurodegenerative
mutations, such as dynactin subunit 1 and diseases, including a variety of ataxias, and
tubulin alpha-4A chain, suggest that another leads to aggregation of the mutant protein
pathway to dysfunctional and destroyed motor (Polling, Hill, & Hatters, 2012). Although protein
neurons is disruption of axonal transport. misfolding or aggregation can apparently result
Genes associated with familial PD include in neurotoxic entities, the mutant mRNA can
those encoding Parkin, an E3 ubiquitin ligase, also play a role in pathogenesis (Wojciechowska
and PTEN-induced putative kinase 1 (PINK1), & Krzyzosiak, 2011). This is particularly true for
a mitochondrial-associated kinase (Lubbe & certain rare neurodegenerative diseases in
Morris, 2014). These two proteins apparently which nucleotide repeat expansion occurs in
work together to regulate mitophagy, the deg- noncoding regions of a gene.
radation of defective mitochondria via autop- Prion diseases are unique in that they can be
hagy. PD-associated recessive PINK1 and contracted via proteinaceous infectious parti-
Parkin mutations lead to reduced mitophagy, cles (the origin of the term “prion”) (Collinge,
suggesting that neurons of the substantia nigra 2016; Johnson, 2005). Nevertheless, they can
are particularly susceptible to mitochondrial also be caused by genetic mutations in the PrP
dysfunction. Dominant mutations in the gene gene, which encodes PrP. These mutations lead
encoding α-synuclein, the protein that deposits to protein aggregation and plaque formation in
in the characteristic Lewy bodies in PD, also the brain. Different mutations can lead to dif-
cause familial PD. This discovery provided ferent patterns of protease-resistance, different
compelling evidence that misfolded or aggre- brain regions with neurodegeneration, and
gated α-synuclein can trigger PD, especially as different clinical presentations (e.g., CJD, FFI,
duplication or triplication of the wild-type and GSS). These specific effects with specific
α-synuclein gene also leads to familial PD. The mutations are thought to be caused by partic-
gene encoding leucine-rich repeat kinase 2 ular conformational states and glycosylation
(LRRK2) is also a major site of PD-associated patterns in the protein, related to the concept
mutations, not only for dominantly inherited of PrP strains mentioned earlier.

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8 1. SOLVING THE PUZZLE OF NEURODEGENERATION

MOLECULAR CLUES TO understanding of the essential role of PrP in

MECHANISMS OF PATHOGENESIS prion diseases, the identities of the infectious
and lethal forms are unknown, as are the
The identification of proteins in pathological mechanisms of neurotoxicity.
deposits and the discovery of genes associated For AD, the case for Aβ in some form as a
with familial forms of neurodegenerative dis- pathogenic entity is not as air-tight as it is for
eases opened the door to experiments to deter- PrP in prion diseases, but the evidence is never-
mine the normal functions and pathological theless compelling (Selkoe & Hardy, 2016). As
roles of these proteins. mentioned earlier, missense mutations that
For prion diseases, the involvement of PrP is cause autosomal-dominant familial AD are
inescapable (Soto & Satani, 2011). The protein found in and around the Aβ region of APP and
deposits in the brain in the form of amyloid in the catalytic component of the protease
plaques, dominant mutations in the PrP gene that produces Aβ. Aβ is produced from the
cause familial disease, introduction of PrP single-pass membrane protein APP through
from diseased brains causes highly reproduc- two proteolytic events: cleavage outside the
ible and specific disease in the recipient, and membrane by β-secretase, followed by cleavage
knockout of the PrP gene in the recipient pre- of the C-terminal remnant inside its transmem-
vents this "protein-only" disease. brane domain by γ-secretase. Secreted Aβ ranges
Prion diseases have three causes: dominant from 38 to 43 amino acids, with the 40-residue
inheritance of a PrP mutation, spontaneous or peptide (Aβ40) being the major form. The longer
sporadic occurrence, and infection through Aβ42 peptide (Aβ42), containing more of the
environmental exposure (Colby & Prusiner, hydrophobic transmembrane domain, is more
2011). PrP is a membrane-anchored glycopro- aggregation-prone and is the major protein com-
tein, the normal function of which remains ponent of the amyloid plaques of AD.
unknown. The leading hypothesis for the patho- Mutations in APP near the Aβ N-terminus,
genic mechanism of PrP is that it can assume an which cause FAD in midlife, increase cleavage
ensemble of conformations, some of which are by β-secretase, leading to increased Aβ produc-
capable of propagation and templating the con- tion throughout life (Tanzi & Bertram, 2005). In
version of normal cellular PrP to a lethal form. contrast, a protective mutation, also near the Aβ
The propagation of infectious forms can occur N-terminus, that substantially reduces AD risk
over a long incubation period that is essentially in old age decreases this same proteolytic event
independent of PrP expression level. to lower Aβ production throughout life (Jonsson
Upon the leveling off of the prion titer, the et al., 2012). APP mutations within the Aβ region
conversion to lethal PrP and manifestation of increase the propensity of Aβ to aggregate.
disease is inversely proportional to PrP expres- Finally, mutations near the C-terminus of the Aβ
sion: disease onset occurs faster in PrP- region in APP alter cleavage by γ-secretase to
overexpressing transgenic mice than in wild- increase the proportion of aggregation-prone
type mice, and wild-type mice develop disease peptides (Tanzi & Bertram, 2005).
faster than PrP heterozygous knockout mice Mutation in the PSEN1 and PSEN2 genes
(Collinge, 2016). These kinetic findings demon- likewise alter the proportion of aggregation-
strate that prion propagation and toxicity can prone Aβ peptides (Tanzi & Bertram, 2005).
be uncoupled; that is, the infectious prion par- Presenilin is the catalytic component of
ticle is distinct from the lethal form of the pro- γ-secretase, a membrane protein complex that
tein. Despite the clear progress and the carries out hydrolysis within the hydrophobic

THE MOLECULAR AND CELLULAR BASIS OF NEURODEGENERATIVE DISEASES

 MOLECULAR CLUES TO MECHANISMS OF PATHOGENESIS 9
environment of the lipid bilayer. AD-causing that can be elicited by a variety of factors,
mutations in presenilins affect the proteolysis of including pathogenic Aβ.
the APP transmembrane domain by γ-secretase As mentioned earlier, familial FTD can also
to generate longer, more aggregation-prone Aβ result from dominant mutations in the PRG
peptides. gene, located very near the MAPT gene. These
As with prion diseases, however, the patho- mutations lead to truncated transcripts that
genic entity in AD remains at large. The amy- undergo nonsense-mediated delay (Baker et al.,
loid plaques per se do not correlate with 2006; Cruts et al., 2006). How heterozygous loss
neurodegeneration, and the current leading of PRG leads to FTD is unclear. These mutations
hypothesis is that oligomeric forms of Aβ42 are are not associated with tau pathology, but rather
synaptotoxic (Benilova, Karran, & De Strooper, with neuronal deposition of the RNA-binding
2012). Oligomers from dimers and trimers to protein TDP-43. TDP-43 deposits are seen in a
dodecamers and larger have been touted as the spectrum of neurodegenerative diseases with
primary pathogenic species, but the high het- FTD on one end and ALS on the other, and
erogeneity makes it challenging to deconvolute together these are referred to as TDP-43 protei-
and identify a single molecular culprit. One nopathies (Geser et al., 2010). Pathological TDP-
possibility is that an “Aβ soup”, with many 43 translocates from the nucleus to the cyto-
toxic forms, is responsible. How pathogenic Aβ plasm, where it aggregates in a hyperpho-
triggers pathological tau and neurofibrillary sphorylated, ubiquitinated, and truncated form
tangles also remains unknown. Roles for risk (Neumann et al., 2006). However, TDP-43 is an
factors APOE and TREM2 are also unclear, RNA-binding protein, and aberrant RNA pro-
although both of these proteins are apparently cessing may be the main driver of pathogenesis,
involved in Aβ clearance (Castellano et al., rather than toxic TDP-43 protein aggregates
2011; Wang et al., 2015). (Janssens & Van Broeckhoven, 2013).
In AD, tau pathology correlates better with FTD-ALS TDP-43 pathology is also seen
degree of cognitive impairment than does Aβ with dominant mutations in the TARPBP gene,
pathology (Ballatore et al., 2007). This finding encoding TDP-43, as well as with repeat expan-
is consistent with Aβ being a pathogenic trig- sion of an intronic region of the c9orf72 gene.
ger, with tau being downstream in the process Hypotheses for how c9orf72 repeat expansion
and temporally and spatially more proximal to causes neurodegeneration include (1) haploin-
neuronal cell death. While mutations that sufficiency, in which loss of expression from
cause familial AD are found in the substrate the mutant allele leads to reduction of function
and the enzyme that produce Aβ, AD- below a critical threshold; (2) aggregation of
associated mutations in the tau gene (MAPT) the expanded mRNA into inclusions that
have not been identified. However, mutations sequester proteins critical to RNA processing
in tau do cause familial forms of FTD, demon- and function; (3) non-ATG-initiated translation
strating that altered tau protein alone can lead of this repeat-expanded region into different
to tau pathology, neurodegeneration, and aggregation-prone dipeptide-repeat proteins
dementia (Wolfe, 2009). Such findings support (Haeusler et al., 2016). Protein aggregation also
a central role for tau in AD pathogenesis as occurs with ALS-mutant SOD1, and in general,
well. Tau pathology is seen in a variety of ALS is associated with an inability to clear mis-
neurodegenerative diseases, including chronic folded or aggregated proteins from motor neu-
traumatic encephalopathy (Lee et al., 2001; rons (Ruegsegger & Saxena, 2016).
McKee et al., 2009). Apparently, pathological Like motor neurons, dopaminergic neurons
tau is a common mediator of neurodegeneration in the substantia nigra are also apparently

THE MOLECULAR AND CELLULAR BASIS OF NEURODEGENERATIVE DISEASES

10 1. SOLVING THE PUZZLE OF NEURODEGENERATION

highly vulnerable to a variety of molecular system can become overwhelmed. Moreover,

insults, as a number of different genes are asso- mHtt can cause impaired energy metabolism
ciated with familial PD (Kalia & Lang, 2015; by interfering with mitochondrial function,
Lubbe & Morris, 2014). Misfolded and/or biogenesis, and quality control by mitophagy.
aggregated α-synuclein is a common feature Why mHtt particularly affects medium spiny
and is elicited by mutation, duplication, or trip- neurons of the striatum is unclear, although
lication of the α-synuclein gene. α-Synuclein, enhanced excitotoxicity of these glutaminergic
which normally is associated with synaptic neurons is a leading hypothesis.
vesicles, forms inclusions in sporadic PD as RNA toxicity is also implicated as a contrib-
well. Other mutations lead to mitochondrial utor to HD pathogenesis (Marti, 2016). The
dysfunction. PD proteins Parkin and PINK1 CAG triplet repeat expansion can form hairpin
normally work together to signal defective structures that bind nuclear proteins, leading to
mitochondria that require disposal through altered RNA splicing, disrupted nuclear export,
mitophagy (Nguyen, Padman, & Lazarou, and nucleolar stress. The contributions to path-
2016). PINK1 accumulates on the surface of ogenicity from the mHTT transcript can be dif-
defective mitochondria, which leads to the ficult to separate from those elicited by the
recruitment and activation of Parkin, an E3 polyglutamine-expanded protein. However,
ubiquitin ligase. Parkin then ubiquitinates pro- the presence of triplet repeat expansion in non-
teins in the outer mitochondrial membrane to coding regions of other genes can lead to
trigger autophagy of the organelle. More gen- degenerative diseases, including myotonic dys-
erally, a number of gene products associated trophy 1, HD-like 2, and spinocerebellar ataxia
with PD play important roles in vesicle traf- 8, which are caused by CTG expansion in non-
ficking, particularly to lysosomes, and defects coding regions of DMPK, JPH3, and ATXN8
in these proteins can lead to the inability to genes, respectively. Moreover, expression of
clear misfolded and aggregated proteins as translated and untranslated mHtt exon 1
well as defective mitochondria (Abeliovich & mRNA containing the expanded CAG tract in
Gitler, 2016). human neuronal cell lines demonstrated a
Although HD is a 100% monogenetic neuro- purely mRNA-mediated neurotoxicity (Banez-
degenerative disease, its mechanisms of patho- Coronel et al., 2012; Sun et al., 2015). Evidence
genesis are quite complex (Labbadia & that folding of the expanded CAG regions in
Morimoto, 2013). The Htt protein, in which mRNA can contribute to disease include the
polyglutamine expansion occurs, has a large finding that interruption of such CAG tracks
interactome that couples it to many different with the synonymous CAA codon can mitigate
cellular processes. The mutant form of Htt neurodegeneration in Drosophila (Li, Yu, Teng,
(mHtt) causes widespread changes in the tran- & Bonini, 2008).
scriptome, and consistent with this finding,
mHtt interacts with and disrupts a number of
proteins involved in general transcription. COMMON THEMES AND
Moreover, mHtt also disrupts the function of CONTROVERSIES IN
histone acetyltransferases, which are critical NEURODEGENERATION
regulators of gene expression. The mutant pro-
tein also affects general proteostasis, prevent- Given the above findings on the pathology,
ing proper folding by interfering with genetics, and mechanisms of pathogenesis for
chaperones and disrupting degradation via the the major neurodegenerative diseases, some
proteasome. Thus, the general protein disposal general principles for the molecular and

THE MOLECULAR AND CELLULAR BASIS OF NEURODEGENERATIVE DISEASES

 COMMON THEMES AND CONTROVERSIES IN NEURODEGENERATION 11
cellular basis of pathogenesis and progression containing misfolded and aggregated PrP
can be appreciated (Fig. 1.1). Some of these serves as a template to convert normal cellular
concepts are still controversial, with robust PrP into this same misfolded and aggregated
debate in the field. conformation, increasing the titer of infectious
Perhaps the most important emerging con- particles in the brain. Ultimately, misfolded
cept is that of prion-like spread of pathogenic and/or aggregated PrP serves as a template to
protein seeds in various neurodegenerative convert cellular PrP into a lethal form. As men-
diseases (Collinge, 2016). Prion diseases are tioned above, the kinetics of prion titer buildup
rare and work by a paradigm-shifting mecha- and disease onset and progression demonstrate
nism of protein-only transmission from organ- that the infectious and lethal forms of PrP can
ism to organism. An infectious protein seed be dissociated.

FIGURE 1.1 Molecular and cellular mechanisms of neurodegeneration. Multiple factors are known to contribute to
the pathogenesis and progression of neurodegenerative diseases. Among these include the following: (1) Genetic muta-
tions, either dominant or recessive, are associated with familial forms of all the major neurodegenerative diseases.
(2) Huntington’s disease and other nucleotide repeat disorders express mutant mRNAs that can form hairpins and other
structures that sequester RNA-binding proteins and alter mRNA metabolism and function. (3) Disease-associated proteins
can misfold and aggregate into neurotoxic forms. (4) Misfolded proteins are not adequately degraded through the
ubiquitin-proteasome system. (5) Aggregated proteins are not adequately degraded via autophagy. (6) Mitochondrial
dysfunction and inadequate mitophagy can result in release of apoptotic signals and formation of ROS and altered energy
metabolism. (7) Axonal transport can be blocked by aggregated proteins or mutant transport proteins. (8) Synaptic
transmission of pathogenic protein seeds can spread protein pathology from neuron to neuron. (9) Activated microglia or
(10) astrocytes release neurotoxic signals and ROS. ROS, reactive oxygen species.

THE MOLECULAR AND CELLULAR BASIS OF NEURODEGENERATIVE DISEASES

12 1. SOLVING THE PUZZLE OF NEURODEGENERATION

In other neurodegenerative diseases, some be appropriate, as it is unclear whether these

of the proteins implicated in pathogenesis and ultimately manifest themselves as distinct dis-
progression appear capable of propagating eases, as clearly occurs with PrP and the prion
their misfolded and aggregated states through diseases.
transsynaptic propagation, spreading poten- Regardless of the nature of the spread of the
tially pathogenic seeds through a neuronal net- protein pathology, the accumulation of misfolded
work (Guo & Lee, 2014). In this hypothesis, and/or aggregated proteins is responsible for it.
specific disease manifestation results from the But how does such accumulation occur? One
anatomical location of the initiating pathogenic reason is the inability of the protein folding
seed and how the neurons are integrated into machinery to handle the disease-associated
neural circuits. This concept has major implica- protein (Lindberg et al., 2015). Indeed, overex-
tions, not only for understanding disease pression of molecular chaperones and foldases
mechanisms but also for developing new strat- can prevent protein aggregation and neurode-
egies for the discovery and development of generation in animal models of disease. The
potential therapeutic agents for disease preven- inability to properly fold disease-associated
tion and treatment (Hasegawa, Nonaka, & proteins and prevent them from aggregating
Masuda-Suzukake, 2017). can then overwhelm the protein disposal
Despite some apparent similarities, the anal- mechanisms. As misfolded protein accumulates
ogy between PrP in prion diseases and proteins inside the neuron, the capacity of the ubiquitin-
such as Aβ, tau, and α-synuclein and others in proteasome system to degrade proteins is com-
AD, FTD, PD, and other neurodegenerative promised (Ciechanover & Brundin, 2003).
diseases is limited, and framing these other These in turn can build up and lead to general
proteins as “prion-like” is problematic (Walsh proteotoxicity. Similarly, as the disease-
& Selkoe, 2016). To call the spread of patho- associated protein aggregates, the autophagic
genic particles from neuron to neuron “trans- machinery must work harder to dispose of
mission” is misleading to the degree that it these aggregates, interfering with the ability to
alludes to a concept from infectious disease clear out other waste, including dysfunctional
that means contagion from one organism to mitochondria (Nixon, 2013). As mentioned
another. In this context, the spread from neu- before, the unique characteristics of neurons
ron to neuron is more akin to the concept of make them highly vulnerable to cellular stress,
synaptic transmission in neuronal signaling. and this includes proteotoxic stress. Protein
The term “trans-synaptic propagation” more aggregates can clog axons, blocking the trans-
accurately describes the process (Liu et al., port of vital macromolecules and organelles
2012). Interestingly, pathogenic PrP itself does between the cell body and synaptic termini
not clearly propagate from neuron to neuron in (Morfini et al., 2009). Synapses may be directly
a network-like manner. affected by protein aggregates as well, and fail-
Evidence continues to build for the transsy- ure of synaptic function can ultimately lead to
naptic propagation of certain pathological pro- neurodegeneration (Haass & Selkoe, 2007).
teins, especially for tau and α-synuclein (Guo Neurons also use considerable energy to
& Lee, 2014). Even the concept of different carry out their critical functions and therefore
strains is under consideration, with some of need functional mitochondria. As just pointed
these pathological proteins apparently misfold- out, overwhelming the autophagic machinery
ing and aggregating into distinct states that are with aggregated protein can interfere with
capable of propagation. Calling these different mitochondrial quality control through mito-
aggregated states “strains”, however, may not phagy (Yerbury et al., 2016). Moreover, axonal

THE MOLECULAR AND CELLULAR BASIS OF NEURODEGENERATIVE DISEASES