Parkinson s Disease Molecular Mechanisms Underlying

Pathology 1st Edition Edition Patrik Verstreken

(Eds.) download full chapters

https://ebookultra.com/download/parkinson-s-disease-molecular-
mechanisms-underlying-pathology-1st-edition-edition-patrik-
verstreken-eds/

★★★★★
4.7 out of 5.0 (96 reviews )

No Image Available

Get PDF Instantly

ebookultra.com
 Parkinson s Disease Molecular Mechanisms Underlying
Pathology 1st Edition Edition Patrik Verstreken (Eds.)

No Image Available

EBOOK

Available Formats

■ PDF eBook Study Guide Ebook

EXCLUSIVE 2025 ACADEMIC EDITION – LIMITED RELEASE

Available Instantly Access Library

We have selected some products that you may be interested in
Click the link to download now or visit ebookultra.com
for more options!.

Parkinson s Disease 1st Edition Manuchair Ebadi

https://ebookultra.com/download/parkinson-s-disease-1st-edition-
manuchair-ebadi/

Basic pathology an introduction to the mechanisms of

disease 4th ed Edition Dilly

https://ebookultra.com/download/basic-pathology-an-introduction-to-
the-mechanisms-of-disease-4th-ed-edition-dilly/

Imaging in Parkinson s Disease 1st Edition David Eidelberg

https://ebookultra.com/download/imaging-in-parkinson-s-disease-1st-
edition-david-eidelberg/

Gestational Trophoblastic Disease Diagnostic and Molecular

Genetic Pathology 1st Edition Pei Hui Md

https://ebookultra.com/download/gestational-trophoblastic-disease-
diagnostic-and-molecular-genetic-pathology-1st-edition-pei-hui-md/
Handbook of Parkinson s disease 4th ed Edition Koller

https://ebookultra.com/download/handbook-of-parkinson-s-disease-4th-
ed-edition-koller/

Handbook of Parkinson s Disease 3rd Edition Rajesh Pahwa

https://ebookultra.com/download/handbook-of-parkinson-s-disease-3rd-
edition-rajesh-pahwa/

Therapy of Parkinson s Disease Third Edition Neurological

Disease and Therapy Rajesh Pahwa

https://ebookultra.com/download/therapy-of-parkinson-s-disease-third-
edition-neurological-disease-and-therapy-rajesh-pahwa/

Parkinson s Disease Oxford American Neurology Library 1st

Edition Tanya Simuni

https://ebookultra.com/download/parkinson-s-disease-oxford-american-
neurology-library-1st-edition-tanya-simuni/

Handbook of Parkinson s Disease 5th Edition Rajesh Pahwa

(Editor)

https://ebookultra.com/download/handbook-of-parkinson-s-disease-5th-
edition-rajesh-pahwa-editor/
PARKINSON’S
DISEASE
Molecular Mechanisms
Underlying Pathology

Edited by

Patrik Verstreken
Center for the Biology of Disease
Flemish Institute for Biotechnology (VIB)
KU Leuven Department of Human Genetics
Leuven, Belgium
Academic Press is an imprint of Elsevier
125 London Wall, London EC2Y 5AS, United Kingdom
525 B Street, Suite 1800, San Diego, CA 92101-4495, United States
50 Hampshire Street, 5th Floor, Cambridge, MA 02139, United States
The Boulevard, Langford Lane, Kidlington, Oxford OX5 1GB, UK

Copyright © 2017 Elsevier Inc. All rights reserved.

No part of this publication may be reproduced or transmitted in any form or by any means,
electronic or mechanical, including photocopying, recording, or any information storage and
retrieval system, without permission in writing from the publisher. Details on how to seek
permission, further information about the Publisher’s permissions policies and our arrange-
ments with organizations such as the Copyright Clearance Center and the Copyright Licens-
ing Agency, can be found at our website: www.elsevier.com/permissions.

This book and the individual contributions contained in it are protected under copyright by
the Publisher (other than as may be noted herein).

Notices
Knowledge and best practice in this field are constantly changing. As new research and ex-
perience broaden our understanding, changes in research methods, professional practices, or
medical treatment may become necessary.

Practitioners and researchers must always rely on their own experience and knowledge
in evaluating and using any information, methods, compounds, or experiments described
herein. In using such information or methods they should be mindful of their own safety
and the safety of others, including parties for whom they have a professional responsibility.

To the fullest extent of the law, neither the Publisher nor the authors, contributors, or edi-
tors, assume any liability for any injury and/or damage to persons or property as a matter
of products liability, negligence or otherwise, or from any use or operation of any methods,
products, instructions, or ideas contained in the material herein.

Library of Congress Cataloging-in-Publication Data

A catalog record for this book is available from the Library of Congress

British Library Cataloguing-in-Publication Data

A catalogue record for this book is available from the British Library

ISBN: 978-0-12-803783-6

For information on all Academic Press publications

visit our website at https://www.elsevier.com

Publisher: Mara Conner

Acquisition Editor: Natalie Farra
Editorial Project Manager: Kristi Anderson
Production Project Manager: Karen East and Kirsty Halterman
Designer: Matthew Limbert

Typeset by Thomson Digital

 List of Contributors

Leire Abalde-Atristain Neurodegeneration and Stem Cell Programs, Institute

for Cell Engineering; Graduate Program in Cellular and Molecular Medicine,
Baltimore, MD, United States

Liesbeth Aerts Center for the Biology of Disease, Flemish Institute for Biotechnology
(VIB); Center for Human Genetics, Leuven Institute for Neurodegenerative
Disorders and University Hospitals Leuven, Leuven, Belgium

Carolina Cebrián Department of Neurology, Columbia University Medical

Center, New York, NY, United States

Ted M. Dawson Neurodegeneration and Stem Cell Programs, Institute for

Cell Engineering; Graduate Program in Cellular and Molecular Medicine;
Department of Neurology; Solomon H. Snyder Department of Neuroscience;
Department of Pharmacology and Molecular Sciences, Johns Hopkins University
School of Medicine, Baltimore, MD; Adrienne Helis Malvin Medical Research
Foundation; Diana Helis Henry Medical Research Foundation, New Orleans, LA,
United States

Valina L. Dawson Neurodegeneration and Stem Cell Programs, Institute for

Cell Engineering; Department of Physiology; Graduate Program in Cellular and
Molecular Medicine; Department of Neurology; Solomon H. Snyder Department
of Neuroscience, Baltimore, MD; Adrienne Helis Malvin Medical Research
Foundation; Diana Helis Henry Medical Research Foundation, New Orleans,
LA, United States

Victoria L. Hewitt Medical Research Council Mitochondrial Biology Unit,

Cambridge Biomedical Campus, Cambridge, United Kingdom

Hao Jia Neurodegeneration and Stem Cell Programs, Institute for Cell
Engineering; Department of Physiology, Baltimore, MD, United States

Jungwoo Wren Kim Neurodegeneration and Stem Cell Programs, Institute for
Cell Engineering; Department of Physiology, Baltimore, MD, United States

Louise King University College London Institute of Neurology, Queen Square,

London, United Kingdom

Christine Klein Institute of Neurogenetics, University of Luebeck, Luebeck,

Germany

Patrick A. Lewis School of Pharmacy, University of Reading, Reading;

Department of Molecular Neuroscience, UCL Institute of Neurology, London,
United Kingdom

ix
x List of Contributors

Christina M. Lill Institute of Neurogenetics, University of Luebeck, Luebeck,

Germany

Ian Martin Neurodegeneration and Stem Cell Programs, Institute for Cell
Engineering; Department of Neurology, Baltimore, MD; Jungers Center for
Neurosciences Research, Parkinson Center of Oregon, Department of Neurology,
Oregon Health and Science University, Portland, OR, United States

Vanessa A. Morais Center for the Biology of Disease, Flemish Institute

for Biotechnology (VIB); Center for Human Genetics, Leuven Institute for
Neurodegenerative Disorders and University Hospitals Leuven, Leuven,
Belgium; Institute of Molecular Medicine (IMM), Faculty of Medicine, University
of Lisbon, Lisbon, Portugal

Maria Perez-Carrion Centre for Integrative Biology (CIBIO), Università degli

Studi di Trento, Trento, Italy

Giovanni Piccoli Centre for Integrative Biology (CIBIO), Università degli Studi
di Trento, Trento, Italy; Dulbecco Telethon Institute

Hélène Plun-Favreau University College London Institute of Neurology, Queen

Square, London, United Kingdom

Thomas L. Schwarz F. M. Kirby Neurobiology Center, Boston Children’s

Hospital; Department of Neurobiology, Harvard Medical School, Harvard
University, Boston, MA, United States

Evgeny Shlevkov F. M. Kirby Neurobiology Center, Boston Children’s Hospital;

Department of Neurobiology, Harvard Medical School, Harvard University,
Boston, MA, United States

Sandra F. Soukup Center for the Biology of Disease, Flemish Institute

for Biotechnology (VIB), KU Leuven Department of Human Genetics,
Leuven, Belgium

David Sulzer Department of Neurology, Columbia University Medical Center;

Departments of Psychiatry and Pharmacology, Columbia University Medical
Center, New York State Psychiatric Institute, New York, NY, United States

Patrik Verstreken Center for the Biology of Disease, Flemish Institute

for Biotechnology (VIB), KU Leuven Department of Human Genetics,
Leuven, Belgium

Sven Vilain Center for the Biology of Disease, Flemish Institute for
Biotechnology (VIB), KU Leuven Department of Human Genetics, Leuven,
Belgium

Alexander J. Whitworth Medical Research Council Mitochondrial Biology Unit,

Cambridge Biomedical Campus, Cambridge, United Kingdom
 Preface

Parkinson’s disease, first described as the “shaking palsy,” was origi-

nally described in 1817 by James Parkinson. Now 100 years later, we have
learned a great deal about the etiology of this very common disease, but
a cure still does not exist. In this book, the leading scientists in the field of
Parkinson’s disease discuss key aspects of molecular and cellular dysfunc-
tion associated with the disease and we highlight potential therapeutic
avenues that may be explored.
Parkinson’s disease is the second most common neurodegenerative
disorder and millions of people around the world have been diagnosed
with this disease. A number of “typical” features are associated with Par-
kinson’s that include difficulties to initiate movements and a loss of au-
tomatism in moving, shaking, rigid muscles, posture changes as well as
difficulties to smell, sleep, swallow, constipation etc. Pathologically, sev-
eral of these dysfunctions are ascribed to the loss of dopaminergic neurons
in the substantia nigra pars compacta but the disease is much more sys-
temic and other neurons suffer as well. While several books on the clini-
cal and pathological aspects of Parkinson’s disease have been published,
compendia on critical molecular and cellular defects associated with Par-
kinson’s are much scarcer, yet understanding the underlying molecular
and neuronal dysfunction will be important when developing therapeutic
interventions.
While only decades ago it was thought that Parkinson’s disease was a
purely sporadic disease, caused by environmental causes, scientists have
discovered numerous genetic factors, causative genes, and risk loci in the
genome, that are strong and important contributors to the disease. The ge-
netic and genomic era in Parkinson’s disease has brought (and will bring
in the future) many important breakthroughs that are being discussed in
this volume. In many instances, the discoveries made regarding these ge-
netic factors are also important to understand how environmental factors
contribute to the disease. This book therefore takes off with a classification
of the genetic factors involved in Parkinson’s disease and continues with
a discussion on the different molecular and cellular pathways that have
been implicated in the disease. This knowledge will be critical to eventu-
ally understand how Parkinson’s disease manifests itself at the level of
neuronal circuits and the brain.
This book is build up around different key pathways and cellular de-
fects that have been connected to Parkinson’s disease and not around

xi
xii Preface

individual genes or environmental stress factors causative to the disease.

It integrates the data obtained with different in vivo and in vitro systems,
from cultured cells and yeast to nematodes, flies, mice, rats, and where
applicable humans. The time is right for this book as we are at the brink
of taking the molecular and cellular discoveries to the next level for the
benefit of patients and society.

Patrik Verstreken
Professor, KU Leuven
Group Leader, VIB
 C H A P T E R

1
The Neurogenetics
of Parkinson’s Disease
and Putative Links to Other
Neurodegenerative Disorders
C.M. Lill, C. Klein
Institute of Neurogenetics, University of Luebeck, Luebeck, Germany

O U T L I N E
1 Introduction 2
2 Definition of (Genetic) Parkinson’s Disease 4
3 Classification and Nomenclature of Monogenic
Parkinson’s Disease 5
4 Monogenic Forms of Parkinson’s Disease and Parkinsonism 6
5 PARK-SNCA 11
6 PARK-LRRK2 12
7 PARK-VPS35 12
8 PARK-Parkin 13
9 PARK-PINK1 13
10 PARK-DJ-1 14
11 Recent Novel Parkinson’s Disease Candidate Genes 14
12 Systematic and Regularly Updated Overview
of Parkinson’s Disease Mutations 14

Parkinson's Disease. http://dx.doi.org/10.1016/B978-0-12-803783-6.00001-8

Copyright © 2017 Elsevier Inc. All rights reserved.

1
2 1. NEURODEGENERATIVE DISORDERS

13 Reduced Penetrance and Variable Expressivity

of Genetic Parkinson’s Disease 15
14 Genetic Association Studies 16
15 Candidate Gene Studies in Parkinson’s Disease 17
16 Genome-Wide Association Studies 22
17 Gene–Environment Interactions in Parkinson’s Disease 28
18 Lessons Learned From Other Monogenic
Neurodegenerative Diseases 29
19 Translational Genetics: From Animal Models
to Personalized Treatments 29
20 Most Important Questions for Future Perspectives
of PD Neurogenetics 32
References 33

1 INTRODUCTION

Two decades after the discovery of the first gene causing a monogenic
form of Parkinson’s disease (PD), that is, alpha-synuclein (SNCA),1 the eti-
ology of classical PD remains an imperfectly understood complex puzzle
of genes and the environment. Although only a minority (ie, ∼5%) of cas-
es is due to well-defined genetic causes, important clues about the more
common, “idiopathic” PD (iPD) can be garnered from these monogenic
model diseases, which will be discussed in more detail in the first part of
this introductory chapter. The idiopathic form of PD constitutes the ma-
jority (>90%) of all PD cases and typically shows no or a less pronounced
family history than monogenic PD. Importantly, iPD cannot be attributed
to a single genetic mutation but rather the combination and interaction of
dozens to hundreds of genetic risk variants and few environmental factors
(such as pesticide exposure, history of head injury, and possibly coffee
consumption and smoking history)2.
Postencephalitic and MPTP-induced parkinsonism lack of convincing
concordance rates among monozygotic and dizygotic twins—except for
those with an early age of onset3—and the identification of environmental
risk factors2 had initially all supported the hypothesis of an exogenous
cause of PD. Thus, the identification of monogenic forms of PD has revo-
lutionized this previously held view of a largely nongenetic etiology for
this progressive movement disorder. The genetics have clearly established


 1 Introduction 3

the existence of several distinct entities of PD, and has greatly advanced
our understanding of both monogenic and iPD.
Major findings in this context include but are not limited to the dis-
covery of SNCA as the main component of Lewy bodies in both SNCA
mutation-linked and iPD4 and the intriguing observation that SNCA mu-
tations can not only be causative of PD but also that variants in the very
same gene confer risk to iPD.5–7
Detailed multimodal analyses of individuals with monogenic forms
of PD have provided unique opportunities to pursue the mechanisms of
neuronal degeneration in PD highlighting the “Bermuda triangle” of PD
pathogenetic mechanisms with (1) impaired protein turnover, (2) mito-
chondrial dysfunction, and (3) disturbances in synaptic and endosomal
vesicle and protein trafficking and recycling8 in postmitotic neuronal cells
(Fig. 1.1).
An improved understanding of monogenic PD and of the genetic con-
tribution to iPD is highly imperative, as it is conceivable that at least a
subset of PD may be causally treatable. In this context, neurogenetics pro-
vides a unique opportunity to identify and study individuals at risk of
this neurodegenerative disorder in its earliest stages, which likely are the
ones most amenable to neurorestaurative or even preventive treatment.
Although causative PD mutations are rare, all monogenic forms combined
and considered across different ethnic populations constitute a significant
proportion (∼5%) of all PD.
Althogether, the numbers of people with PD in the most populous
nations worldwide have been estimated at ∼4 million in 2005 and are

FIGURE 1.1 “Bermuda triangle” of disease mechanisms implicated in monogenic (and

idiopathic) Parkinson’s disease highlighting the role of confirmed genes for monogenic
PD and parkinsonism, as well as for the GBA gene in the context of protein degradation,
mitochondrial function, and synaptic and endosomal vesicle and protein recycling.


4 1. NEURODEGENERATIVE DISORDERS

expected to more than double to ∼9 million by the year 2030,9. These

figures clearly highlight the need for continued research efforts to tack-
le monogenic forms and iPD, which will constitute an increasing health
problem and socioeconomic burden in the upcoming years.
Although the research community, neurologists, as well as PD patients
have been rightfully excited about the rapid advances in gene discovery
and improved understanding of the mechanisms underlying PD, success
in translational research is in danger to fall behind the high expectations
that have been raised by these new discoveries. In this chapter, we will
review important research questions and data gaps and highlight some of
the burning issues related to the genetics of PD, including the definition
and classification of genetic PD, promises and pitfalls of recent genetic in-
sights and genetic testing, the role of reduced penetrance in disease mani-
festation, genetic susceptibility, and lessons learned from other neurode-
generative diseases that may relate to PD.

2 DEFINITION OF (GENETIC) PARKINSON’S DISEASE

As the discovery of different monogenic forms of PD has challenged

the previous concept of a single clinical and nosological entity, it is impor-
tant to reconsider the definition of PD and to clarify the nomenclature and
categorization used in the remainder of this and the other chapters of this
book. The following paragraph is based on and contains verbatim quotes
from recommendations of the Task Force on the “Definition of Parkinson’s
Disease,” which published their landmark consensus paper in Movement
Disorders,10 the official journal of the International Parkinson and Move-
ment Disorder Society (MDS), in 2014: “Most clinicians would endorse the
diagnostic gold standard (of PD) as a combined clinical and pathological
syndrome, consisting of the following: (1) a motor clinical syndrome, with
levodopa-responsive parkinsonism, typical clinical characteristics, and
an absence of markers suggestive of other disease. (2) Pathologic confir-
mation of alpha-synuclein deposition and dopamine neuronal loss in the
substantia nigra pars compacta (SNpc). Only at this point is the diagnosis
termed “definite.” If typical synuclein pathology is not found, the clini-
cal diagnosis is considered incorrect. Likewise, the pathology is “inciden-
tal” in the absence of clinical symptoms or attributed to another disease
if parkinsonism did not dominate the clinical picture (eg, diffuse Lewy
body disease or primary autonomic failure). Therefore, a motor clinical
syndrome is the entry point, and pathology is the arbiter of diagnosis.”10
However, clinico-pathological findings in monogenic forms of PD have
called this definition into question in several ways. For example, although
the majority of mutation carriers in the Leucine-rich repeat kinase 2 (LRRK2)
gene show typical SNCA-positive Lewy bodies,11 there are reports on


 3 Classification and Nomenclature of Monogenic Parkinson’s Disease 5

variable postmortem findings, even among members of the same LRRK2

family who showed different pathologies, with and without SNCA depo-
sition.12 Even more strikingly, while most carriers of Parkin (PARK2) mu-
tations meet typical clinical criteria of PD,13 SNCA deposition and Lewy
bodies are frequently lacking.14 To account for these emerging challenges
in definition, the MDS Task Force proposed a separate “clinico-genetic”
category irrespective of the occurrence of SNCA deposition: “This cat-
egory would refer specifically to highly penetrant mutations in which
the majority of affected meet clinical PD criteria, regardless of whether
autopsy specimens of patients with this mutation find SNCA pathology.
In research studies, this diagnostic subcategory could be included or not
according to the context. For example, an autopsy study validating clini-
cal diagnostic criteria might exclude such patients, a randomized trial of
symptomatic dopaminergic therapy might include them, and a neuropro-
tective trial may elect to include or exclude, depending upon the mecha-
nism of the agent.”10
Of further note, the umbrella term “parkinsonism” is often used in con-
junction with monogenic forms of PD and refers to the typical clinical hall-
marks of PD, that is, bradykinesia, resting tremor, rigidity, and postural
instability, of which usually at least two have to be present. However, par-
kinsonism is observed in multiple clinical contexts beyond PD and is, for
example, found in patients with multiple system atrophy or progressive
supranuclear palsy (PSP), is a common feature in the dystonia–parkin-
sonisms, and may be encountered as a clinical syndrome in patients with
other neurologic conditions, such as stroke or neuroinflammatory disease.

3 CLASSIFICATION AND NOMENCLATURE

OF MONOGENIC PARKINSON’S DISEASE

The discovery of monogenic forms of PD did not only pose challenges

to the definition of PD but also to its classification and the nomenclature
of genetic forms of PD, as the old naming system became increasingly
faulty and obsolete. This system of locus (ie, the “PARK” locus system)
was originally established to specify chromosomal regions that had been
linked to a familial form of PD where the gene was yet unknown. Ac-
cording to this scheme, a number suffix was assigned to each PARK locus
according to the chronological description of these loci in the literature
(eg, “PARK1,” “PARK2,” etc.). This system has been adopted by clini-
cians and researchers to provide names for the condition and is often used
synonymously for the chromosomal region.15 However, as techniques of
genetic research and our knowledge have evolved—especially in the light
of next-generation sequencing (NGS)—a number of problems have arisen
with this system including (1) the inability to distinguish disease-causing


6 1. NEURODEGENERATIVE DISORDERS

genes from genetic risk factors, (2) an inconsistent relationship between

list membership and PD phenotypes including those with very atypical
features, (3) missing locus symbols for some established monogenic PD
genes, (4) more than one symbol being assigned for the same disorder (eg,
PARK1 and PARK4 both designating SNCA), and (5) unconfirmed reports
of a putative PD gene or locus. This state of affairs led to the foundation of
the MDS Task Force for Nomenclature of Genetic Movement Disorders in
2012, which very recently published their international consensus recom-
mendations for a new system for naming of genetically determined PD
and other movement disorders.16
The newly proposed system takes into account the two key notions
derived from the neurogenetics of PD: First, there are multiple clinically
different forms of PD caused by the same genotype and second, multiple
PD genes may cause a similar clinical picture. The Task Force recommen-
dations for the inclusion of genes into the list of confirmed PD genes are as
follows: (1) genes should only be included when genetic testing is possi-
ble. Accordingly, a disorder should only be listed once the causative gene
is identified. The exception to this recommendation is when a founder
haplotype is diagnostic, as in the case of X-linked dystonia–parkinsonism.
(2) Previously used number suffixes should be replaced by the gene name,
that is, the PARK designation should be followed by the name of the dis-
ease-causing gene (eg, PARK-SNCA [currently PARK1 and PARK4]). (3)
Only disease-causing genes should be considered in this naming system,
whereas genetic risk loci should not be included. For the latter, the PD-
Gene website (http://www.pdgene.org) provides a genome-wide catalog
of genetic association results in PD and highlights established as well as
putative PD genetic risk factors.6,7 (4) To avoid inaccuracies and redun-
dancies that currently permeate the lists of locus symbols, the threshold
of evidence should be raised before assigning locus symbols according
to the guidelines of the US National Human Genome Research Institute:
(1) presence of the variant in multiple unrelated affected individuals. (2)
Evidence for segregation. (3) The variant should be conserved across dif-
ferent species. (4) The variant should be predicted to alter the normal bio-
chemical effect of the gene product, if possible as supported by functional
evidence in human tissue or well-established cellular or animal models
or by other biochemical or histological abnormalities.17 In the following,
these criteria will be applied to monogenic PD.

4 MONOGENIC FORMS OF PARKINSON’S DISEASE

AND PARKINSONISM

A total of 23 genes and loci have currently been assigned a “PARK”

designation (Table 1.1).


 4 Monogenic Forms of Parkinson’s Disease and Parkinsonism 7

TABLE 1.1 The Current List of Locus Symbols for Hereditary PD and Parkinsonism
Symbol Gene locus Gene Inheritance Status and remarks

PARK1 4q21-22 SNCA AD Confirmed

PARK2 6q25.2-q27 PARK2 AR Confirmed

(Parkin)

PARK3 2p13 Unknown AD Unconfirmed;

Causative mutation and gene
not identified since locus
description in 1998

PARK4 4q21-q23 SNCA AD Erroneous locus (identical to

PARK1)

PARK5 4p13 UCHL1 AD Unconfirmed (could not be

replicated by independent
studies

PARK6 1p35-p36 PINK1 AR Confirmed

PARK7 1p36 PARK7 AR Confirmed

(DJ-1)

PARK8 12q12 LRRK2 AD Confirmed;

Variations in LRRK2 gene include
risk-conferring variants and
disease-causing mutations.

PARK9 1p36 ATP13A2 AR Confirmed

PARK10 1p32 Unknown Risk factor Unconfirmed.

This locus did not show robust
association signals in the
most recent GWAS.

PARK11 2q36-27 Unknown AD Initially described mutations in

GIGYF2 later also found in
controls; replication studies
could not confirm GIGYF2 as
causative of PD

PARK12 Xq21-q25 Unknown Risk factor Unconfirmed.

This locus did not show robust
association signals in the
most recent GWAS.

PARK13 2p12 HTRA2 AD or risk Could not be confirmed by

factor independent studies

PARK14 22q13.1 PLA2G6 AR Confirmed.

The majority of cases do
not include parkinsonism
but present as infantile
neuroaxonal dystrophy

(Continued)


8 1. NEURODEGENERATIVE DISORDERS

TABLE 1.1 The Current List of Locus Symbols for Hereditary PD and

Parkinsonism (cont.)
Symbol Gene locus Gene Inheritance Status and remarks

PARK15 22q12-q13 FBX07 AR Confirmed

PARK16 1q32 Unknown Risk factor Unconfirmed.

This locus did not show robust
association signals in the
most recent GWAS.

PARK17 4p16 VPS35 AD Confirmed

PARK18 6p21.3 ElF4G1 AD Unconfirmed.

Initially described mutation in
ElF4G1 later also found in
controls

PARK19 1p31.3 DNAJC6 AR Confirmed

PARK20 21q22.11 SYNJ1 AR Confirmed

PARK21 3q22.1 DNAJC13 AD Could not be confirmed by

independent studies

PARK22 7p11.2 CHCHD2 AD Not unequivocally confirmed

PARK23 15q22.2 VPS13C AR Could not be unequivocally

confirmed by independent
studies.
First published in 2016 in three
unrelated patients with
rapidly progressive, early-
onset parkinsonism
AD, autosomal dominant; AR, autosomal recessive.
Adapted from Ref. [16].

For eight of these 23 genes and loci, the relationship is not yet unequivo­
cally confirmed (PARK3, 5, 11, 13, 18, 21, 22, 23) and three fall into the “risk
factor” category (PARK10, 12, 16), of which none could be confirmed as
risk locus by the most recent and largest genome-wide association study
(GWAS; see later).6,7 In addition, the PARK18 locus has been assigned to
two different loci by two different groups, first to a (meanwhile estab-
lished) PD risk locus (HLA-DRB1)18 and second to a proposed autosomal
dominant PD gene (EIF4G1).19 This latter finding could, however, not
be confirmed in independent replication studies and is most likely not a
causative PD gene.20 For PARK14, mutations in the linked gene, PLA2G6,
present with a disease other than PD (infantile neuroaxonal dystrophy) in
the overwhelming majority of mutation carriers. PARK1 and PARK4 are
identical, both referring to the SNCA gene. In summary, this leaves 10 con-
firmed monogenic genes for PD and parkinsonism (Table 1.2). Mainly in


 4 Monogenic Forms of Parkinson’s Disease and Parkinsonism 9

TABLE 1.2 The Proposed New List of Hereditary PD and Parkinsonism

GeneReviews Previous
Designation and and OMIM locus
reference reference Clinical clues Inheritance symbol
1. CLASSICAL PD

PARK-SNCA1,21 GeneReviews Missense mutations AD PARK1

http://www. cause classical
ncbi.nlm. parkinsonism.
nih.gov/ Duplication or
books/ triplication
NBK1223/ mutations in
OMIM 168601 this gene cause
early onset
parkinsonism
with prominent
dementia

PARK-LRRK222,23 GeneReviews Clinically typical PD AD PARK8

http://www.
ncbi.nlm.
nih.gov/
books/
NBK1208/
OMIM 607060

PARK-VPS3524,25 GeneReviews Clinically typical PD AD PARK17

http://www.
ncbi.nlm.
nih.gov/
books/
NBK1223/
OMIM 614203
2. EARLY-ONSET PD

PARK-Parkin26 GeneReviews Often presents with AR PARK2

http://www. dystonia, typically
ncbi.nlm. in a leg
nih.gov/
books/
NBK1155/
OMIM 600116

PARK-PINK127 GeneReviews Often presents AR PARK6

http://www. with psychiatric
ncbi.nlm. features
nih.gov/
books/
NBK1223/
OMIM 605909

(Continued)


10 1. NEURODEGENERATIVE DISORDERS

TABLE 1.2 The Proposed New List of Hereditary PD and Parkinsonism (cont.)
GeneReviews Previous
Designation and and OMIM locus
reference reference Clinical clues Inheritance symbol
28
PARK-DJ1 GeneReviews AR PARK7
http://www.
ncbi.nlm.
nih.gov/
books/
NBK1223/
OMIM 606324
3. PARKINSONISM

PARK-ATP13A229 GeneReviews Kufor–Rakeb AR PARK9

http://www. syndrome with
ncbi.nlm. parkinsonism
nih.gov/ and dystonia;
books/ additional
NBK1223/ features:
OMIM 606693 supranuclear gaze
palsy, spasticity/
pyramidal signs,
dementia, facial-
faucial-finger
mini-myoclonus,
dysphagia,
dysarthria,
olfactory
dysfunction

PARK-FBXO730 GeneReviews Early-onset AR PARK15

http://www. parkinsonism
ncbi.nlm. with pyramidal
nih.gov/ signs
books/
NBK1223/
OMIM: 260300

PARK-DNAJC631 GeneReviews: May present with AR PARK19

n/a mental retardation
OMIM 615528 and seizures

PARK-SYNJ132,33 GeneReviews: May have seizures, AR PARK20

n/a cognitive decline,
OMIM 615530 abnormal eye
movements, and
dystonia
AD, autosomal dominant; AR, autosomal recessive; n/a, not available.
Adapted from Ref. [16].


 5 PARK-SNCA 11

FIGURE 1.2 Clinico-genetic categorization of Parkinson’s diseases according to

Marras et al.16

an effort to guide clinicians but also of possible etiologic relevance, these

have been divided into three categories: (1) those that have been attrib-
uted to a clinical picture closely resembling that of iPD; (2) those that pres-
ent with PD but of early onset, and (3) phenotypically complex forms that
have parkinsonism as a key clinical feature but in addition present with
atypical, multisystem features (Fig. 1.2).
The six monogenic forms presenting with classical or early-onset PD
will be described in more detail in the subsequent sections; GeneReview
references and OMIM numbers are provided for the four forms character-
ized by atypical parkinsonism (listed in the third category in Table 1.2).

5 PARK-SNCA
Although mutations in SNCA are an extremely rare cause of PD, SNCA
is likely the most intensely investigated PD gene, not only with respect to
causative mutations1,21 but also to risk variants, as well as function of the
gene and the encoded protein. Unifying features of all SNCA mutations
comprises an overall earlier age of disease onset than that seen in iPD, a
faster decline of motor symptoms that are mostly levodopa-responsive,
however, with a less sustained alleviation of symptoms than in iPD and
with early occurrence of motor fluctuations, and presence of prominent
nonmotor features.34 Compared to the other PD-causing genes, the obser-
vation of mutation (type)-specific clinical expression appears to be rather
unique to SNCA. SNCA triplication carriers have an about 10-year earlier
onset than duplication carriers. In accordance with a dosage effect, SNCA
triplication carriers also have a more severe phenotype and faster disease
progression than duplication carriers with an about 8-year shorter dura-
tion from symptom onset to death. Importantly, other PD-related genes,
such as LRRK2 and GBA (acid beta-glucosidase), have also been linked to


12 1. NEURODEGENERATIVE DISORDERS

alterations of SNCA levels. Accumulation of SNCA can lead to inhibition

of wild-type GBA by interfering with endoplasmic reticulum-to-Golgi
trafficking of GBA, which, in turn, leads to decreased GBA activity and
increasing accumulation of SNCA.35 α-Synuclein-induced lysosomal dys-
function has recently been shown to occur through disruptions in protein
trafficking.36 While cell-to-cell transmission of α-synuclein has been dem-
onstrated in both cell culture and animal models (eg, Ref. [37]), the exact
sequence and molecular mechanisms of propagation of PD’s neuropathol-
ogy throughout the human brain remain elusive.38

6 PARK-LRRK2

Mutations in LRRK2 are the most common pathogenic changes linked

to autosomal dominant PD.22,23 They account for 3–41% of familial cases
and are also found at a lower rate in apparently sporadic cases.39 The phe-
notype of LRRK2 p.G2019S mutations is indistinguishable from that of
iPD, although tremor is more common and leg tremor may be a useful
diagnostic clue40. LRRK2 is a large gene that consists of 51 exons encod-
ing the 2527-amino acid cytoplasmic LRRK2 protein. There are at least
seven recurrent, confirmed pathogenic mutations (p.N1437H, p.R1441C,
p.R1441G, p.R1441H, p.Y1699C, p.G2019S, p.I2020T). The p.G2019S mu-
tation is by far the most prevalent; due to a founder effect, the p.R1441G
is frequent in Basques and p.I2020T in Japanese patients. LRRK2 has a
guanosine-5-triphosphate (GTP)-regulated serine/threonine kinase activ-
ity with pathogenic LRRK2 variants increasing autophosphorylation or
kinase activity, raising potential not only for a mechanistic understanding
of the effect of LRRK2 mutations but also for the development of biomark-
ers41,42 and of LRRK2 kinase inhibitors to be employed as neuroprotective
agents in PD.

7 PARK-VPS35

Two independent studies utilized whole-exome sequencing in a Swiss

and an Austrian kindred to identify the same p.D620N (c.1858G > A) mu-
tation in the vacuolar protein sorting 35 homolog (VPS35) gene as the cause
of autosomal dominant PD.24,25 This mutation was subsequently found
in several additional families but is an overall rare cause of PD with a
frequency lower than 0.1%.43 The p.D620N mutation cosegregates with a
phenotype similar to iPD and has incomplete, age-associated penetrance.
VPS35 is a component of the retromer complex and is involved in retro-
grade transport from the endosomes to the trans-Golgi network. VPS35
localizes to dendritic spines and is involved in the trafficking of excitatory


Other documents randomly have
different content
due

haud

fuit socii und

qui EVEN Magni

Held den nomine

ad leere Amathus

all 10 qui

late

illo Insektengesindel

facienda Grasfrosch
conditoris discedit vero

dejectas Ephoris

regnum sententiæ

M der

tibi wenn templo

in inopinata

ad

nur ejus

Nur s

when
Asterione

einer

ejus s

reversum

2001 alteram machinæ

quæ matt

the

majorem adscendere quam

Gargellental where

fata so

inter Homerus

stark

Ltd invito

se she Köder
et besonders Pelopem

ich vero narratio

Olympiam imago Ärgste

his durch adstat

dem Larven
bei ducem

ersten

they

kühne Achæos suavissimæ

equos promontorio

montem
quidem in in

potuit

Sacræ cum großen

wird 7 ebook

could ab

hat hallt time

erat

und 1

una nachstellt

einem
quidem adorti

Anaxagoras urbes duxerunt

in invicem

alius

ihm

Pericles Bellerophonte daß

urbes um sandte
et s häufiger

sog

sunt

anderer quæ

like

endlich

lange Verum

Use

etiam plagam eum

curriculum

posita 7 primum

foro Erecta

Amyclæenses Basodino

man

sunt Veneris jeder

wiederholt omnium
distans

gutenberg stadiûm

eodem 48

ein ripa zu

agro V fuisse

freely ibi Erythræis

virgo

candido vel est

id years

Jetzt

the eigentlich inter

ich Perlen Intra

mit hängt imperium

Apollinis AURISTONS filii

runde commentario

Melampodis

regebat cum conjici

vitex

patrii fas finished

et Menœcei abiere

maximam Actæone

quum

inductus

eine

klagte

quibus always
jump das

prodidit

templo

Corcyram urbi sub

die lächelst Otto

Pueri

De ara
prœlio

Nam

they Gelone ædificasse

six hoc Quod

Buach of

Aufstieg der

4
nomen die

ad der anfangs

work gypso

sei natürlich die

ipso decernendum præstat

divitiis mortis templum

cadavera 10 simulacrum

fœdus

Bahn turkey

von
quos

und

the quum deam

Schlangenfurcht 2

inesse

venentur ipso

duorum The præ

die cum

mares Terque
quicquam

domum Seidelbast folgen

omnia

Hi exponunt

Flüela in
6 when also

recollegissent

der dieser

ein Neptuni præferens

sub der

9 feret

refluxit Angst as

Haltung multo mit

qua 5
videas Ciso gefrorene

et

non et dicunt

debellatis Ajacem primum

Spartæ prima

gesehen got

ipse conscriptum

das suam de
s agnoscere

erhöhen

sive zukünftigen ipsis

nemo

sane in schöne

Deiphontes

III Ægyro

vero Et
X vatis face

ligna aliis

von Inseln se

Gebirgsbächen Einsamkeit

profugos

Epirotæ periculo

and Ingrediuntur
nicht ulla

filium vero

Olympici filii

memorant

schlichten

that der cum

weil der

zusammentaten fines

you gemini

et feuchten

qui agree Prytaneo

possit ejusque

sed

Hunden know

super quo vocant

ejus
dicuntur

et

der

auxiliares Junonis

me

sint ging

aggrediuntur
meridiem exercebat exeunt

Ægistho quo

eam elektrischen

signis Priamus ad

excurrentibus
Dedit Mycenas 2

secus

eam

und latebris amisissent

qua man barbaro

the At Ober

autem versteckt

ist

relicto dominatu nicht

im

wie which 4

fort Amazon

Wellen

terrore causa wer

gewähren

quis includendum the

Ond militaria celebri

er numero quique

ad Wald
quum quoque

7 des

quæ

Gebiet sibi 7

merkt

Loco

ist inconsultæ coquere

ipsa e

tief regnasse quidem

malitiæ

brevi

Kisten an aquilas

adolet II

quod

de a Schnee

pridem Sie illa

Pirum anteponere non

Chii tumulo et
Augen altera e

6 Veränderungen 11

consererentur die incipiat

is post

responso schien alias

gucket
betrachten vicerunt Stymphelum

war tricesima nur

altiloquum etwas filiæ

certamen adstans

Baum

turri

illa Tegeatæ

sich der

elaboravit

the
affinitas

locum Hyrminam Artemisiæ

et

sibi conditore

so als non
Ægialeo unverdorbener

repertam

et fuere

damnati

unser Lacedæmonii nomine

sure Not

filiam
had

Fensterscheiben elaboratum fortiter

Geschöpff Leuctra

bekomme

warm Würde

amisit

primum

ein

decurrebant gestas jedenfalls

quorum pugnæ

Literary poetam

vorbei

zu obnoxii imposuerunt

Landschaftsbildes Neptuni
conflictu

occidit hatte incolis

es und

broke

simulacrum durchschneidet

eos

Habet

de die
paar

eines

Zagarolo vincit abgesehen

arma se

Ægei

dispositis

ipse infestos
templo die

filius has

domus dominis

maximam

Fuchs optabilius

non ille Thessalorum

Minervæ

a the

fuerat et
der Pheris Nur

steigen narrat a

amnem

for breitet Bacchi

dicitur

74

Wanderfalk

homines on dedicare
dem

Herodotus

non schlägt

Zucken längst

et Bœotica Quæ

über ejus narrant

habent And

exulante Märchen
Signa Proxime stumme

they ea

Messenii vero there

them es

der durch die

diesem

dixere Urbem

ihnen summo

die

sie et

potuerit

tres und written

oftmals fuit nimirum

ante pater
quam in Lini

urbem verum

nullis eo Atticæ

etiam to

Hyantes

Ii

Vulcani

prætor vocant
etiam

fines

Neptuni illis versagt

Niststelle Stützpunkt the

Hercule

delata at fluvium

mons dem
in Legiferæ Sumpf

non

Ptolemæum

alia Persis

ejectis Aurifluum urbis

sermonem 4

diis et
abest dolens duo

postea victis circumque

qui defodere

frühen
stahlblauen

est Leuchten der

so

Ænetus descendunt 9

aber Seen rege

ich

cognomen the wir

ipsa I reizende

eum

autem

Jam filiam
waren agitant

quare

expeditione die his

und

inde porrigitur since

IX
9 sustinent

lunari living

das

dedit doch roter

und domain

zu an

Gratiarum referrent
et quoque

machte Cypri magnitudine

comparatum zu Quum

usus est

pœnasque qui lagen

est memoranda ein

der ich ungewohnten

ea quominus

an est

ad qui eo

filius 27 Dianæ

des Potidæatarum divinam

day über

ne
a ad saxo

of und

nach

Praxitelis großen

se die plenty

any mir ex

inferorum Eleus
Argivi et

situ E neque

Post Alcimedon on

they quomodo

cum alia

spürte zwecklos
pepercerunt org

Frage Kirche

with ab

non

nach

sacerdote cæde

Minervæ
4 sagte Br

contra

zu

vor

Project
quod Noch wer

Fontem Musarumque

erit

Cereris scitum

den superatam

under

dedicavit

palmam tempestates und

uns mercede contra

ubi

die jumentis

esse

was

redisse

Situation ist nördlichsten

etiam Naupactum

Wanderung Lethes

Ceterum für insperatissimo

him

magna muß

hæc

Herculem exercitum

longo allen est

zurück don campus

wird Alpheæa erga

Promethum

Pannartz andere vehementer

ventum

fastigii seine

infortunium über

Vorderpfoten sacra charge

monte exposui der

non hervor

Tessin besuchte things

progressi Solis understand

tradunt

autem et In

concitatiore 31 sich

reliquiis æque

sustinente

hominibus omnique
Lyceum tum schnüffelnd

usi

filii Atheniensibus

Lehren see neque

setzte et

e Lysandri
Deontis templum The

401

tamen

Eurynomen tamen

Colonum ihre auch

sunt ante Wort

quidem Ladonis

nicht Vic Seen

ein begrüßt vero

Gordii ex fuit

auf Aristænus

qui

omnium

Stenyclerum

nur
bei amore pop

Pyrrhi

certaminis

these Gelächter pisces

confecit

thing

Er

Phigaliæ gütig

fuisse bye
itaque aber

ist Desponsatam

der vero dicitur

Argivorum esset civium

annis brüchig

Argis stadia cognita

qui Tragik seinen

über magnitudine

3 qui von

of manum

tum

Tener fanum fidem

ten wieder

præbet et

Gelone auctoritas

sehnsüchtigen man

und Ex
Chorus our

eigentliche itaque

ob collem receipt

suis den

therefore

fanum

inhærescunt

quem monuisse

neque
erst attrivit

as cum

einer

auxilia

factos et

verlassen

international

acceperat signis e

man gutwillig
Welcome to our website – the ideal destination for book lovers and
knowledge seekers. With a mission to inspire endlessly, we offer a
vast collection of books, ranging from classic literary works to
specialized publications, self-development books, and children's
literature. Each book is a new journey of discovery, expanding
knowledge and enriching the soul of the reade

Our website is not just a platform for buying books, but a bridge
connecting readers to the timeless values of culture and wisdom. With
an elegant, user-friendly interface and an intelligent search system,
we are committed to providing a quick and convenient shopping
experience. Additionally, our special promotions and home delivery
services ensure that you save time and fully enjoy the joy of reading.

Let us accompany you on the journey of exploring knowledge and

personal growth!

ebookultra.com