Content uploaded by Sobia Zaidi
Author content
All content in this area was uploaded by Sobia Zaidi on Nov 19, 2018
Content may be subject to copyright.
Full Terms & Conditions of access and use can be found at
http://www.tandfonline.com/action/journalInformation?journalCode=ines20
International Journal of Neuroscience
ISSN: 0020-7454 (Print) 1543-5245 (Online) Journal homepage: http://www.tandfonline.com/loi/ines20
Protein aggregation, misfolding and consequential
human neurodegenerative diseases
Neha Sami, Safikur Rahman, Vijay Kumar, Sobia Zaidi, Asimul Islam, Sher Ali,
Faizan Ahmad & Md. Imtaiyaz Hassan
To cite this article: Neha Sami, Safikur Rahman, Vijay Kumar, Sobia Zaidi, Asimul Islam, Sher Ali,
Faizan Ahmad & Md. Imtaiyaz Hassan (2017) Protein aggregation, misfolding and consequential
human neurodegenerative diseases, International Journal of Neuroscience, 127:11, 1047-1057,
DOI: 10.1080/00207454.2017.1286339
To link to this article: https://doi.org/10.1080/00207454.2017.1286339
Accepted author version posted online: 23
Jan 2017.
Published online: 08 Feb 2017.
Submit your article to this journal
Article views: 298
View Crossmark data
Citing articles: 3 View citing articles
ORIGINAL ARTICLE
Protein aggregation, misfolding and consequential human neurodegenerative
diseases
Neha Sami
1
*,Safikur Rahman
2
*, Vijay Kumar
1
, Sobia Zaidi
1
, Asimul Islam
1
, Sher Ali
1
, Faizan Ahmad
1
and
Md. Imtaiyaz Hassan
1
1
Centre for Interdisciplinary Research in Basic Sciences, Jamia Millia Islamia, New Delhi, India;
2
Department of Medical Biotechnology,
Yeungnam University, Gyeongsan, South Korea
ARTICLE HISTORY
Received 24 October 2016
Revised 20 January 2017
Accepted 20 January 2017
Published online 8 February
2017
ABSTRACT
Proteins are major components of the biological functions in a cell. Biology demands that a protein
must fold into its stable three-dimensional structure to become functional. In an unfavorable
cellular environment, protein may get misfolded resulting in its aggregation. These conformational
disorders are directly related to the tissue damage resulting in cellular dysfunction giving rise to
different diseases. This way, several neurodegenerative diseases such as Alzheimer, Parkinson
Huntington diseases and amyotrophic lateral sclerosis are caused. Misfolding of the protein is
prevented by innate molecular chaperones of different classes. It is envisaged that work on this line
is likely to translate the knowledge into the development of possible strategies for early diagnosis
and efficient management of such related human diseases. The present review deals with the
human neurodegenerative diseases caused due to the protein misfolding highlighting
pathomechanisms and therapeutic intervention.
KEYWORDS
Protein misfolding;
aggregation; amyloids;
pathomechanisms;
amyotrophic lateral sclerosis;
stem cell
Introduction
Proteins are the nitrogenous organic compounds
involved in all the cellular and immunological processes
providing support to the structure and function of differ-
ent tissues of the body [1]. As per the cellular require-
ment, a protein may act alone or as a part of signaling
cascades encompassing intermolecular interactions [2].
The protein functions are based on their three-dimen-
sional structure which involves protein folding [3,4].
Protein folding is an intricate process requiring a func-
tional and thermodynamically stable structure resulting
in its unique conformation. Unlike ideal in vitro condi-
tions, protein folding in crowded cellular environment
requires constantly quality check [5,6]. Any error during
folding is circumvented by protein quality control (PQC)
system [7], of which molecular chaperones are the first-
hand molecules. In spite of the constitutive support
of molecular chaperones, proteins may still undergo
misfolding [8].
During protein folding, certain emergency responses
like unfolded protein response or heat shock response
are activated to maintain protein homeostasis [9]. The
first priority of these responses is to refold the misfolded
protein. However, when the protein is irreparable, the
same is directed toward degradation employing ubiqui-
tin proteasome system or autophagosome–lysosome
pathway [10]. Due to erroneous PQC pathways, some-
time these misfolded proteins persist in the cell, undergo
aggregation [11] and eventually accumulates causing
many diseases including neurodegeneration [12]. There
is a set mechanism of PQC that operates meticulously in
the cell system (Figure 1).
Protein misfolding can be driven by many factors
such as mutations, failure of the proteostasis network,
errors in the post-translational modifications or traffick-
ing of proteins, and certain environmental factors
[13,14,15]. The partially folded or misfolded proteins typ-
ically expose their hydrophobic amino acid residues and
unstructured regions of polypeptide backbone to the
solvent that facilitates aggregation. The aggregation pro-
cess is driven by hydrophobic forces as seen in protein
folding and is highly concentration dependent [16].
This review describes the current molecular under-
standing of the mechanism of protein aggregation with
an emphasis on amyloid formation. In addition, attempts
have been made to highlight possible pathomechanisms
of neurodegenerative disease and involvement of stem-
cell-based therapeutic intervention.
CONTACT Md. Imtaiyaz Hassan mihassan@jmi.ac.in
*Equally contributed
© 2017 Informa UK Limited, trading as Taylor & Francis Group
INTERNATIONAL JOURNAL OF NEUROSCIENCE, 2017
VOL. 127, NO. 11, 1047–1057
http://dx.doi.org/10.1080/00207454.2017.1286339
Mechanism of protein aggregation
Whenever a protein gets exposed to unfavorable condi-
tions such as high temperature, extremes of pH, high
pressure and agitation, it loses its native conformation
and succumbs to denaturation [17–19]. Unfolded state
of protein in aqueous solution is non-functional, unsta-
ble and thermodynamically unfavorable. So, to attain
stability they tend to form aggregate by minimizing their
energy levels [20]. The rate of aggregation is a second-
order reaction depending on the concentration of inter-
acting polypeptide chains as confirmed with small pepti-
des that form fibers [21]. In these peptides, monomeric
state is favored at low concentration, whereas aggre-
gates are formed at relatively higher concentration of
the protein. Aggregation of protein molecules consists
of two components and is best explained by “seeding-
nucleation”model [13]. The first phase is a slow process
called nucleation that involves formation of oligomers,
and the second one is called elongation phase, in which
these oligomers consecutively join to form protofibrils
and fibrils.
The protein becomes loosely packed in the unfolded
state and exposing its hydrophobic core that interacts
with the cellular environment and undergoes self-aggre-
gation [22]. These aggregates are rich in b-sheets,
accommodating a large number of polypeptides to form
protofibrils and fibrils [23]. The seeding-nucleation
model explains that oligomers are the foremost stable
polymer that promotes protein misfolding in an expo-
nential manner. These oligomers are considered as
“seeds”,“aggregation nuclei”or “precursor cores”of
aggregation [24] that provides a template for the revers-
ible attachment of other misfolded proteins to the grow-
ing core [25]. Nucleation is a slow process in which a
small number of misfolded proteins (oligomers) are
formed [26]. When the aggregation core (nucleus)
reaches the level of critical mass, the protein molecules
start attaching to the nucleus irreversibly at a faster rate
culminating into large aggregate referred to as elonga-
tion phase [27]. On the basis of both nucleation and the
exponential aggregation processes, linear and exponen-
tial growth models (i.e. growth from the surface,
Figure 1. The protein quality control system.
1048 N. SAMI ET AL.
fragmentation, or bifurcation) have been developed to
study the dynamics of amyloidogenesis [28].
The “linear growth model”explains the formation of
amyloids as a successive, straight and reversible reaction
that follows a sigmoidal growth kinetics [29]. According
to this model, primary nucleation is a lag phase event
(the time spent in oligomerization; t
lag
), which is fol-
lowed by an exponential phase involving steep transi-
tion zone in which fibrils are formed at a faster rate. The
duration of the exponential phase is termed transition
time (t
tr
) which is very small in the case of amyloid for-
mation as compared to the nucleation. The ratio of lag
time to the transition time is called relative lag time, L
rel
,
that explains the kinetics of linear growth in an efficient
manner. For linear growth, L
rel
is less than 0.2 and it is
independent of initial concentration of monomers (see
Figure 2)[23]. The size of the nuclei of Abpeptides can
be correctly calculated by using L
rel
,t
lag
and t
tr
. Dovid-
chenko et al. [28] suggested that it is important to per-
form a series of kinetic experiments to determine the
sizes of the primary and secondary nuclei of Abpeptides.
The exponential growth model suggests the amyloid
formation as an irreversible reaction that is initiated by
the monomer unit involved in aggregation [28]. The
fragmentation model was first used to describe the
kinetics of actin filament formation [30]. According to
bifurcation model, the process of fibril formation is a
branching reaction where the secondary nucleus is
attached to the inner parts of polymer initiating its
growth [28].
Structural features of amyloids
Amyloids are composed of repetitive and tightly inter-
acting pairs of intermolecular b-sheets, which form the
cross-b-sheet structure [31]. Biophysicists consider amy-
loids as denatured protein aggregates and associate
them with microbial and cellular functions [32]. Studies
have shown that many proteins form amyloid fibrils
which can either be functional or pathological [33–36].
More than 40 proteins are known to form pathogenic
amyloid fibrils whereas only some functional amyloid
fibrils have been reported [37,38]. Several atomic-resolu-
tion X-ray structures of amyloid fibrils formed by short
peptide segments of amyloid have been determined
recently [39–43]. These structures of amyloid fibrils
reveal a peculiar cross-b-sheet motif that consists of a
pair of repetitive b-sheets. When viewed along the axis
of the protofilament, the two b-sheets interlinked to
each other through the side chains of the strands resem-
bles the teeth of a zipper. Hence, the cross-b-sheet motif
has also been termed as the “steric zipper”. The interface
between the two sheets is devoid of water in almost all
structures. The stability of the fibrils depends on several
Figure 2. Kinetics of amyloid formation.
INTERNATIONAL JOURNAL OF NEUROSCIENCE 1049
factors: (i) hydrogen bonds formed between the back-
bone amide groups that run up and down of the
b-sheets, (ii) van der Waals interactions that develop
between the closely interacting pairs of b-sheets, and
(iii) the increased entropy of water molecules is released
from the inner faces of the two b-sheets.
The effects of amyloids can be explained by biochem-
ical properties. The first being the change of phase of
the amyloid-forming proteins from soluble monomers to
insoluble fibrils which disrupts the normal cell function-
ing, either due to loss of a crucial function or gain of a
toxic function. For example, the tumor-suppressor func-
tion of p53 is lost due to its aggregation [44,45]. Similarly,
the HET-s prion induces refolding of the soluble proteins
into the cell membrane that induces cell death in Podo-
spora anserina [46,47].
The second property is the repetitive structure of
amyloids. Once aggregation is triggered in the amyloids,
they can persist indefinitely in cells due to strong inter-
molecular interactions as seen in the case of the HET-s
prion [47]. Its repetitive configuration allows amyloids to
bind to other repetitive biomolecules such as RNA, DNA,
glycosaminoglycans and lipid membranes with a rela-
tively high affinity [48–50]. Moreover, the structural
repetitiveness provides an ideal template for replication
and may therefore be transmissible between cells –or
even infectious in the case of prion diseases [51].
Pathomechanisms of neurodegenerative
diseases
The etiologies of neurodegenerative diseases may be
diverse (Table 1). However, a common pathological sig-
nature is the formation of misfolded protein conformers
and the occurrence of pathogenic proteinaceous depos-
its. Studies based on neurodegenerative-disease-associ-
ated genes have elucidated the two faces of protein
misfolding and aggregation in neurodegeneration: a
gain of toxic function and a loss of physiological func-
tion, which can even occur in combination [52].
The theory of loss-of-function suggests that neurode-
generation is caused by the loss of normal activity of the
protein due to its misfolding and aggregation. The loss
of neuroprotective factor may be associated with an
increased neuronal vulnerability [53–56]. Despite this
explanation regarding loss of function, the most widely
accepted theory of neurodegeneration is gain of func-
tion. This concept is based on the observation of neuro-
nal apoptosis by aggregates of several misfolded
proteins in vitro [57,58]. Additional support for this
hypothesis comes from experiments with transgenic ani-
mals showing neurodegeneration triggered by the mis-
folded protein [59].
The following section summarizes the two faces of
protein misfolding and aggregation also explaining the
pathomechanism of amyotrophic lateral sclerosis (ALS)
and frontotemporal lobar degeneration (FTLD).
The ALS and FTLD are the known neurodegenerative
disorders characterized by a rapid decline in cognitive
and motor functions. FTLD, being the most common
cause of dementia after Alzheimer’s disease (AD), is spe-
cifically characterized by the focal neurodegeneration in
the frontal and anterior temporal lobes of the brain
[60,61]. ALS is a distressing condition that affects the
motor neurons present in the brain and spinal cord and
is usually fatal due to respiratory paralysis [62]. There is
an emerging evidence that these disorders share mutual
pathological and genetic features. TDP-43 (TAR DNA
binding protein, TARDBP)-positive inclusions have been
detected in patients with ALS or FTLD considered to be a
common hallmark of both the disorders [63,64]. TDP-43
proteinopathies are also involved in other neurodegen-
erative diseases, including AD, tauopathies and Lewy
body disorders characterized by a-synuclein inclusions
[65].
The unique features of TDP-43 proteinopathies
include abnormal ubiquitylation and phosphorylation,
mislocalization of TDP-43 protein, presence of insoluble
TDP-43 inclusions, and loss of normal nuclear TDP-43
expression and function. The description of pathology of
TDP-43 proteinopathies has been reviewed earlier [65–
67]. Despite a seminal progress toward understanding
the TDP-43 pathology in human neurodegenerative dis-
eases, the question whether TDP-43 mediates neurode-
generation through a gain of toxic function or a loss of
normal function still remains unanswered. Recent advan-
ces in TDP-43 research helps in understanding the key
events of TDP43-mediated neurodegenerative diseases
[66–69].
Besides this, overproduction of free radicals can cause
oxidative damage to the cell membrane eventually
Table 1. List of some of the human diseases associated with mis-
folding and aggregation of the proteins.
Disease Proteins involved References
Creutzfeld–Jakob disease Prion protein (PrP) [131]
Huntington’s disease Huntingtin [132]
Alzheimer’s disease b-Amyloid protein [133]
Parkinson’s disease a-Synuclein [134]
Transthyretin amyloidosis Transthyretin,
apolipoprotein A1,
gelsolin
[28]
Fabry a-Galactosidase [135]
Frontotemporal dementia Tau, PSEN, TDP-43, FUS,
C9orf72
[136]
Familial Danish/British dementia ABri/ADan [137,138]
Dentatorebropallidoluysian
atrophy (DRPLA)
Atrophin-1 [139]
Amyotrophic lateral sclerosis SOD1, TDP-43, FUS,
C9orf72, TAF15
[140–142]
1050 N. SAMI ET AL.
leading to the neurodegeneration [70,71]. Reactive oxy-
gen species (ROS) are found to be active in the brain and
neuronal tissue which serve as sources of oxidative stress
[72]. Generally, ROS attack glial cells and neurons leading
to the loss of cell membrane function and apoptosis
[73,74].
Therapeutic intervention in neurodegenerative
diseases
Therapeutic intervention poses a challenge with respect
to preventing or reversing the process of proteinopa-
thies. Fortunately, scientists have succeeded in address-
ing this issue to ameliorate these diseases to a certain
extent [75–78]. Misfolding diseases can be treated by tar-
geting the proteins involved in pathogenesis or by
checking the PQS. The PQS involves a number of chaper-
ones and degradation pathways. Thus, by modulating
the chaperone activity and degradation pathway, pro-
tein conformational disorders may be treated. Moreover,
a better understanding of how they operate as an inte-
grated network is necessary to maximize the positive
effects of therapeutic interventions while minimizing
negative side effects. In this context, the following possi-
ble strategies are under active consideration.
Small molecules
This group includes pharmacological and chemical chap-
erones. As the name suggests, pharmacological chaper-
ones are small molecules of low molecular weight that
specifically bind and stabilize a mutant protein or the
one very prone to misfold. On binding with the proteins,
they induce refolding of protein, stabilize their structure
and help the protein to regain its function [79]. In the
context of possible treatment, 13-residue Ò-sheet
breaker peptides (IPrP13)[80], quinacrine [81] and chlor-
promazine [82] are being used. Likewise, galactonojiry-
mycin derivatives have been used to treat aggregation
leading to b-galactosidosis [83].
Another group of small compounds called chemical
chaperones like dimethyl sulfoxide (DMSO), glycerol and
trimethylamine N-oxide (TMAO) are used to target the
aggregation and formation of amyloids [84]. They stabi-
lize proteins against denaturation and correct folding
defects [85]. Since these chaperones stabilize the native
or partially folded protein, they prevent the formation of
oligomers or amyloids. Unlike pharmacological chaper-
ones, these ones do not bind directly with the proteins
and are effective at higher concentration. Thus, they are
less efficient in comparison to pharmacological chaper-
ones. But recently, they have evoked attention as poten-
tial therapeutic agent to treat neurological diseases.
Aggregation in SOD1, lysozyme and prion proteins can
be inhibited using these chaperones [78].
Immunotherapy
Immunotherapy or antibody therapy is targeted for the
treatment of AD by inhibiting the aggregation of Ab
peptides and lowering the burden on cells caused by
the Abplaques [86]. Different types of immunotherapy
are still under investigation [87]. Monoclonal antibodies
are being raised in animal models by immunizing them
passively against the critical regions of the amyloid that
take part in the process of aggregation [88]. The harmful
protein injected inside the animal model stimulates the
production of antibody which eliminates the aggregated
self-proteins or interferes with their further aggregation
[89]. Recent Phase III clinical trial results justifies that the
monoclonal antibody is a good option for targeting Ab
peptide [90]. Also, they have shown great efficacy in
patients suffering from mild-to-moderate AD. The clinical
studies with solanezumab in patients with mild AD are
still going on [91,92]. Active and passive immunizations
have been done in animal models in the context of treat-
ing AD [93] and prion diseases [94].
In case of active immunization against AD, two
approaches have been tried. In the first approach, the
animal is immunized with full-length Ab(42 amino acids
long) which elicits cellular response and in due course of
time produces anti-Abantibodies. In the second
approach, the animal is injected with an immunoconju-
gate which consists of a small fragment of Aband a car-
rier protein. As a result, T-cells are activated and a strong
response is produced against the region of Abpeptide.
Although some successes have been achieved in the
case of animal models [95], the first human trial has
been discontinued because of the occurrence of an
unanticipated severe meningoencephalitis in patients
[96]. So, the focus of recent research has shifted to pas-
sive immunization in which antibodies specific to the
conformation are generated that recognize structural
epitopes of the misfolded proteins and discriminate
between fibrillar and oligomeric conformation [97]. This
is useful in such patients who may not otherwise show
an immune response to Abadministration. Newer strate-
gies are being adopted to develop novel vaccines to
treat AD which generate immune response against Ab
without any side effects [98].
Uses of compounds that inhibit fibril nuclei formation
are important in order to inhibit the amyloid deposition
in cells and to avoid the cytotoxicity of the soluble
oligomers [99]. O
4
, a semi-synthetic derivative of orcein,
is used to treat amyloid. It binds directly to the region of
Abpeptides which is rich in hydrophobic amino acid
INTERNATIONAL JOURNAL OF NEUROSCIENCE 1051
residues and stabilizes self-assembly process of the pre-
cursor core, b-sheet-rich protofibrils and fibrils. This
method efficiently reduces the amount of the small toxic
Aboligomers in the complex, heterogeneous aggrega-
tion reactions [99].
Gene therapy
Gene therapy is a powerful tool for treating neurodegen-
erative diseases. People are working very hard to
improve on vector design, identification of new vector
serotypes, mode of delivery of gene therapies and iden-
tification of new therapeutic targets [100]. Development
of lentiviral vector system has been implicated to resolve
many issues especially the delivery routes to the nervous
system. Lentiviral vectors can effectively deliver genes to
post-mitotic neuronal cell types and offers long-term
gene expression which can generate high titers and do
not possess any immunological complication [101].
Small inhibitory RNA molecules are also proven as a
promising option for the development of novel thera-
peutic strategies for the treatment of neurodegenerative
disorders. It has been widely tried in animal models of
neurodegenerative diseases such as AD, ALS, Hunting-
ton’s disease (HD) and spinocerebellar ataxia [102].
Because of its beautiful specificity and potency, RNAi
technology has also attracted a considerable interest as
a new class of therapeutic strategy to fight genetic dis-
eases including neurodegenerative one [103].
Stem cells
The complexity of the aggregation poses a challenge as
no effective disease-modifying treatments are available
in case of neurodegenerative diseases. Drug-based ther-
apies are symptomatic and are insufficient to treat such
diseases. Stem cell therapy, on the other hand, seems to
be a promising approach to deal with neurodegenera-
tive diseases [104–106]. Stem cells possess potential to
differentiate into various cells in the body in response to
extracellular signals. Many treatments for neurodegener-
ative diseases have been explored utilizing a variety of
stem cells like induced pluripotent stem cells (iPSCs),
embryonic stem cells (ESCs), neural stem cells (NSCs),
mesenchymal stem cells (MSCs), adipose-tissue-derived
stem cells and umbilical cord stem cells. Here we report
the therapeutic applications of stem cells in diverse neu-
rodegenerative diseases.
Two different approaches have been exploited in this
context. The first one deals with the activation and
recruitment of endogenous stem cells to the repair site,
and the second one is related to the transplantation of
the stem cells to replace the damaged cells. Endogenous
stem cells can be activated and recruited by various
cytokine stimulations followed by neurogenesis which
has been found to improve learning ability and memory
[107]. It has been shown in the mice model of AD that
the recruitment of hematopoietic bone marrow in brain
enhances the learning ability and memory by enhanced
neurogenesis [108]. Further, it was shown that AD symp-
toms are greatly reduced when stem cells are trans-
planted into the brain of the AD animal models
[109,110]. In addition to significant improvement in cog-
nitive and memory activities, a decreased plaque forma-
tion was observed.
NSCs have the potential to differentiate into cell types
of neural lineage such as neurons, astrocytes and oligo-
dendrocytes. NSCs exhibit a site-specific differentiation
when transplanted into the rat brain [111]. They have
been shown to differentiate into dopaminergic (DA) neu-
rons both in vitro and in vivo. Several clinical studies have
shown that NSCs can improve the symptoms in Parkin-
son’s disease (PD) patients [112–114]. It has been reported
that the patients transplanted with NSCs can even discon-
tinue the levodopa drug therapy [115]. ESCs or iPSCs can
also differentiate into DA neurons. When transplanted
into the brain of PD rats, these stem cells showed the
improved rotation behavior [116,117]. Moreover, trans-
plantation of NSCs (derived from ESCs) into the monkey
brains has also restored the normal DA function [118].
In case of HD also, there exists no successful treat-
ments thus far. NSCs can serve as an excellent source to
replace the degenerated neurons that has been shown
in the case of HD rat model [119]. Both ESCs and iPSCs
have been used to derive medium spiny neurons [120]
which help in successful neural circuit development and
integration in animal models [121–123].
ALS is known to affect the motor neurons of the brain
and spinal cord. Stem cells isolated from various sources
such as bone marrow, umbilical cord, hematopoietic tis-
sue, adipose tissue, neural tissue and spinal cord have
been shown to differentiate into motor neurons [124].
Animal models and clinical trials have been encouraging
and brought a ray of hope and immense expectation for
ALS patients. Several preclinical works have been done
by transplanting ESCs, NSCs, MSCs and bone marrow
cells in mouse models of ALS [125–128]. In 2008, human
iPSCs from ALS patients were directed to differentiate
into motor neurons [129].The first FDA-approved trial of
stem-cell-based therapy for ALS was initiated in 2010,
using NSCs from Neural Stem, Inc. Karussis et al. [130]in
the same year reported a clinical trial (Phase I/II) using
MSCs. Although stem-cell-based therapeutics era is just
beginning, each study will aid our current understanding
of the safety, feasibility and efficacy of stem cell thera-
pies for neurodegenerative diseases.
1052 N. SAMI ET AL.
Conclusions
Protein misfolding has evoked a great deal of interests
both of clinician and researchers. The reason is that it has
much wider implications and negative connotation in the
context of human health system. Protein misfolding leads
to the formation of aggregates which are toxic to cells
causing pathogenesis. As the situation stands now, a bet-
ter therapeutic approach with minimal side effects needs
to be developed. In this context, systematic search of
overall mutational load employing genome analysis and
genes implicated with misfolding would prove to be a
rewarding proposition. As of today, our knowledge about
the relationship between the protein misfolding and dis-
ease pathogenesis is still rudimentary particularly in the
context of family history. Any additional efforts on this
line will go a long way to enrich our understanding and
perhaps lessen the suffering of the patients.
Acknowledgements
V. Kumar thanks the Department of Science of Technology
(DST), India, for the award of DST-Fast track fellowship (SB/YS/
LS-161/2014). N. Sami thanks University Grants Commission,
India, for the award of fellowship (MANF-47673). F. Ahmad and
M.I. Hassan gratefully acknowledge the final support from the
DST SERB (EMR/2015/002372), India. S. Ali is grateful to DST
SERB for the award of J. C. Bose National Fellowship.
Declaration of interest
The authors declare no conflict of interests.
DST-Fast track fellowship (SB/YS/LS-161/2014). University
Grants Commission, India (MANF-47673). DST SERB, India (EMR/
2015/002372).
ORCID
Md. Imtaiyaz Hassan http://orcid.org/0000-0002-3663-4940
References
1. Khan FI, Wei DQ, Gu KR, et al. Current updates on com-
puter aided protein modeling and designing. Int J Biol
Macromol 2016;85:48–62. Epub 2016/01/06.
2. Vogel C, Bashton M, Kerrison ND, et al. Structure, function
and evolution of multidomain proteins. Curr Opin Struct
Biol 2004;14:208–16. Epub 2004/04/20.
3. Englander SW, Mayne L. The nature of protein folding
pathways. Proc Natl Acad Sci U S A 2014;111:15873–80.
Epub 2014/10/19.
4. Zaidi S, Hassan MI, Islam A, et al. The role of key residues
in structure, function, and stability of cytochrome-c. Cell
Mol Life Sci 2014;71:229–55. Epub 2013/04/26.
5. Zimmerman SB, Minton AP. Macromolecular crowding: bio-
chemical, biophysical, and physiological consequences.
Annu Rev Biophys Biomol Struct 1993;22:27–65. Epub
1993/01/01.
6. Ellis RJ, Minton AP. Protein aggregation in crowded envi-
ronments. Biol Chem 2006;387:485–97. Epub 2006/06/03.
7. Chen B, Retzlaff M, Roos T, et al. Cellular strategies of pro-
tein quality control. Cold Spring Harb Perspect Biol
2011;3:a004374. Epub 2011/07/13.
8. Vendruscolo M, Knowles TP, Dobson CM. Protein solubil-
ity and protein homeostasis: a generic view of protein
misfolding disorders. Cold Spring Harb Perspect Biol
2011;3. Epub 2011/08/10.
9. Hartl FU, Bracher A, Hayer-Hartl M. Molecular chaperones
in protein folding and proteostasis. Nature 2011;475:324–
32. Epub 2011/07/22.
10. Varshavsky A. The ubiquitin system, an immense realm.
Annu Rev Biochem 2012;81:167–76. Epub 2012/06/06.
11. Wickner S, Maurizi MR, Gottesman S. Posttranslational
quality control: folding, refolding, and degrading pro-
teins. Science 1999;286:1888–93. Epub 1999/12/03.
12. Ihara Y, Morishima-Kawashima M, Nixon R. The ubiquitin-
proteasome system and the autophagic–lysosomal sys-
tem in Alzheimer disease. Cold Spring Harb Perspect Med
2012;2. Epub 2012/08/22.
13. Soto C. Protein misfolding and disease; protein refolding
and therapy. FEBS Lett 2001;498:204–7. Epub 2001/06/20.
14. Kelly JW. Alternative conformations of amyloidogenic
proteins govern their behavior. Curr Opin Struct Biol
1996;6:11–7. Epub 1996/02/01.
15. Kumar V, Kashav T, Islam A, et al. Structural insight into
C9orf72 hexanucleotide repeat expansions: towards new
therapeutic targets in FTD-ALS. Neurochem Int 100:11–
20. Epub 2016/08/20.
16. Kumar V, Sami N, Kashav T, et al. Protein aggregation and
neurodegenerative diseases: from theory to therapy. Eur J
Med Chem 2016. Epub 2016/08/04.
17. Bellotti V, Chiti F. Amyloidogenesis in its biological envi-
ronment: challenging a fundamental issue in protein mis-
folding diseases. Curr Opin Struct Biol 2008;18:771–9.
Epub 2008/10/28.
18. Herczenik E, Gebbink MF. Molecular and cellular aspects
of protein misfolding and disease. FASEB J 2008;22:2115–
33. Epub 2008/02/28.
19. Zhou Z, Fan JB, Zhu HL, et al. Crowded cell-like environ-
ment accelerates the nucleation step of amyloidogenic
protein misfolding. J Biol Chem 2009;284:30148–58. Epub
2009/09/15.
20. Cohen SI, Vendruscolo M, Dobson CM, et al. From macro-
scopic measurements to microscopic mechanisms of pro-
tein aggregation. J Mol Biol 2012;421:160–71. Epub 2012/
03/13.
21. Buell AK, Dobson CM, Knowles TP. The physical chemistry
of the amyloid phenomenon: thermodynamics and kinet-
ics of filamentous protein aggregation. Essays Biochem
2014;56:11–39. Epub 2014/08/19.
22. Hill EK, Krebs B, Goodall DG, et al. Shear flow induces
amyloid fibril formation. Biomacromolecules 2006;7:10–3.
Epub 2006/01/10.
23. Arosio P, Knowles TP, Linse S. On the lag phase in amyloid
fibril formation. Phys Chem Chem Phys 2015;17:7606–18.
Epub 2015/02/27.
24. Astbury WT, Dickinson S, Bailey K. The X-ray interpretation
of denaturation and the structure of the seed globulins.
Biochem J 1935;29:2351–601. Epub 1935/10/01.
25. Stefani M, Dobson CM. Protein aggregation and aggre-
gate toxicity: new insights into protein folding, misfolding
INTERNATIONAL JOURNAL OF NEUROSCIENCE 1053
diseases and biological evolution. J Mol Med (Berl)
2003;81:678–99. Epub 2003/08/28.
26. Carulla N, Zhou M, Giralt E, et al. Structure and intermolec-
ular dynamics of aggregates populated during amyloid
fibril formation studied by hydrogen/deuterium exchange.
Acc Chem Res 2010;43:1072–9. Epub 2010/06/19.
27. Moreno-Gonzalez I, Soto C. Misfolded protein aggregates:
mechanisms, structures and potential for disease trans-
mission. Semin Cell Dev Biol 2011;22:482–7. Epub 2011/
05/17.
28. Dovidchenko NV, Finkelstein AV, Galzitskaya OV. How to
determine the size of folding nuclei of protofibrils from
the concentration dependence of the rate and lag-time
of aggregation. I. Modeling the amyloid protofibril forma-
tion. J Phys Chem B 2014;118:1189–97. Epub 2014/01/11.
29. Oosawa F, Asakura S, Hotta K, et al. GF transformation of
actin as a fibrous condensation. J Polymer Sci
1959;37:323–36.
30. Wegner A. Spontaneous fragmentation of actin filaments
in physiological conditions. Nature 1982;296:266–7. Epub
1982/03/18.
31. Sunde M, Serpell LC, Bartlam M, et al. Common core struc-
ture of amyloid fibrils by synchrotron X-ray diffraction. J
Mol Biol 1997;273:729–39. Epub 1997/11/14.
32. Fowler DM, Koulov AV, Balch WE, et al. Functional amyloid
–from bacteria to humans. Trends Biochem Sci
2007;32:217–24. Epub 2007/04/07.
33. Knowles TP, Vendruscolo M, Dobson CM. The amyloid
state and its association with protein misfolding diseases.
Nat Rev Mol Cell Biol 2014;15:384–96. Epub 2014/05/24.
34. Greenwald J, Riek R. Biology of amyloid: structure, func-
tion, and regulation. Structure 2010;18:1244–60. Epub
2010/10/16.
35. Eisenberg D, Jucker M. The amyloid state of proteins in
human diseases. Cell 2012;148:1188–203. Epub 2012/03/
20.
36. Eisele YS, Monteiro C, Fearns C, et al. Targeting protein
aggregation for the treatment of degenerative diseases.
Nat Rev Drug Discov 2015;14:759–80. Epub 2015/09/05.
37. Maury CP. The emerging concept of functional amyloid. J
Intern Med 2009;265:329–34. Epub 2009/02/12.
38. Maji SK, Perrin MH, Sawaya MR, et al. Functional amyloids
as natural storage of peptide hormones in pituitary secre-
tory granules. Science 2009;325:328–32. Epub 2009/06/
23.
39. Nelson R, Sawaya MR, Balbirnie M, et al. Structure of the
cross-beta spine of amyloid-like fibrils. Nature
2005;435:773–8. Epub 2005/06/10.
40. Sawaya MR, Sambashivan S, Nelson R, et al. Atomic struc-
tures of amyloid cross-beta spines reveal varied steric zip-
pers. Nature 2007;447:453–7. Epub 2007/05/01.
41. Apostol MI, Wiltzius JJ, Sawaya MR, et al. Atomic struc-
tures suggest determinants of transmission barriers in
mammalian prion disease. Biochemistry 2011;50:2456–63.
Epub 2011/02/18.
42. Saelices L, Johnson LM, Liang WY, et al. Uncovering the
mechanism of aggregation of human transthyretin. J Biol
Chem 2015;290:28932–43. Epub 2015/10/16.
43. Rodriguez JA, Ivanova MI, Sawaya MR, et al. Structure of
the toxic core of alpha-synuclein from invisible crystals.
Nature 2015;525:486–90. Epub 2015/09/10.
44. Silva JL, De Moura Gallo CV, Costa DC, et al. Prion-like
aggregation of mutant p53 in cancer. Trends Biochem Sci
2014;39:260–7. Epub 2014/04/30.
45. Ano Bom AP, Rangel LP, Costa DC, et al. Mutant p53
aggregates into prion-like amyloid oligomers and fibrils:
implications for cancer. J Biol Chem 2012;287:28152–62.
Epub 2012/06/21.
46. Riek R, Saupe SJ. The HET-S/s prion motif in the control of
programmed cell death. Cold Spring Harb Perspect Biol
2016;8. Epub 2016/06/30.
47. Seuring C, Greenwald J, Wasmer C, et al. The mechanism
of toxicity in HET-S/HET-s prion incompatibility. PLoS Biol
2012;10:e1001451. Epub 2013/01/10.
48. Wang L, Schubert D, Sawaya MR, et al. Multidimensional
structure-activity relationship of a protein in its aggre-
gated states. Angew Chem Int Ed Engl 2010;49:3904–8.
Epub 2010/04/17.
49. Geoghegan JC, Valdes PA, Orem NR, et al. Selective incor-
poration of polyanionic molecules into hamster prions. J
Biol Chem 2007;282:36341–53. Epub 2007/10/18.
50. Supattapone S. Elucidating the role of cofactors in mam-
malian prion propagation. Prion 2014;8:100–5. Epub
2013/12/25.
51. Prusiner SB. Prions. Proc Natl Acad Sci U S A
1998;95:13363–83. Epub 1998/11/13.
52. Winklhofer KF, Tatzelt J, Haass C. The two faces of protein
misfolding: gain- and loss-of-function in neurodegenera-
tive diseases. EMBO J 2008;27:336–49. Epub 2008/01/25.
53. Baker M, Mackenzie IR, Pickering-Brown SM, et al. Muta-
tions in progranulin cause tau-negative frontotemporal
dementia linked to chromosome 17. Nature
2006;442:916–9. Epub 2006/07/25.
54. De Strooper B. Loss-of-function presenilin mutations in
Alzheimer disease: talking point on the role of presenilin
mutations in Alzheimer disease. EMBO Rep 2007;8:141–6.
Epub 2007/02/03.
55. Exner N, Treske B, Paquet D, et al. Loss-of-function of
human PINK1 results in mitochondrial pathology and can
be rescued by Parkin. J Neurosci 2007;27:12413–8. Epub
2007/11/09.
56. Kepp KP. Alzheimer’s disease due to loss of function: A
new synthesis of the available data. Prog Neurobiol
2016;143:36–60. Epub 2016/06/22.
57. Forloni G, Angeretti N, Chiesa R, et al. Neurotoxicity of a
prion protein fragment. Nature 1993;362:543–6. Epub
1993/04/08.
58. El-Agnaf OM, Jakes R, Curran MD, et al. Aggregates from
mutant and wild-type alpha-synuclein proteins and NAC
peptide induce apoptotic cell death in human neuroblas-
toma cells by formation of beta-sheet and amyloid-like fil-
aments. FEBS Lett 1998;440:71–5. Epub 1998/12/23.
59. Bucciantini M, Giannoni E, Chiti F, et al. Inherent toxicity of
aggregates implies a common mechanism for protein
misfolding diseases. Nature 2002;416:507–11. Epub 2002/
04/05.
60. Perry DC, Miller BL. Frontotemporal dementia. Semin
Neurol 2013;33:336–41. Epub 2013/11/16.
61. Sieben A, Van Langenhove T, Engelborghs S, et al. The
genetics and neuropathology of frontotemporal lobar
degeneration. Acta Neuropathol 2012;124:353–72. Epub
2012/08/15.
1054 N. SAMI ET AL.
62. Mitchell JD, Borasio GD. Amyotrophic lateral sclerosis.
Lancet 2007;369:2031–41. Epub 2007/06/19.
63. Mackenzie IR, Rademakers R, Neumann M. TDP-43 and
FUS in amyotrophic lateral sclerosis and frontotemporal
dementia. Lancet Neurol 2010;9:995–1007. Epub 2010/
09/25.
64. Kumar V, Islam A, Hassan MI, et al. Delineating the rela-
tionship between amyotrophic lateral sclerosis and fron-
totemporal dementia: sequence and structure-based
predictions. Biochim Biophys Acta 2016;1862:1742–54.
Epub 2016/06/19.
65. Geser F, Lee VM, Trojanowski JQ. Amyotrophic lateral scle-
rosis and frontotemporal lobar degeneration: a spectrum
of TDP-43 proteinopathies. Neuropathology 2010;30:103–
12. Epub 2010/01/28.
66. Lee EB, Lee VM, Trojanowski JQ. Gains or losses: molecular
mechanisms of TDP43-mediated neurodegeneration. Nat
Rev Neurosci 2011;13:38–50. Epub 2011/12/01.
67. Halliday G, Bigio EH, Cairns NJ, et al. Mechanisms of dis-
ease in frontotemporal lobar degeneration: gain of func-
tion versus loss of function effects. Acta Neuropathol
2012;124:373–82. Epub 2012/08/11.
68. Cascella R, Capitini C, Fani G, et al. Quantification of the
relative contributions of loss-of-function and gain-of-
function mechanisms in TAR DNA-binding protein 43
(TDP-43) proteinopathies. J Biol Chem 2016;291:19437–
48. Epub 2016/07/23.
69. Xu Z, Yang C. TDP-43 –the key to understanding amyo-
trophic lateral sclerosis. Rare Dis 2014;2:e944443. Epub
2014/01/01.
70. Simonian NA, Coyle JT. Oxidative stress in neurodegener-
ative diseases. Annu Rev Pharmacol Toxicol 1996;36:83–
106. Epub 1996/01/01.
71. Trushina E, McMurray CT. Oxidative stress and mitochon-
drial dysfunction in neurodegenerative diseases. Neuro-
science 2007;145:1233–48. Epub 2007/02/17.
72. Uttara B, Singh AV, Zamboni P, et al. Oxidative stress and
neurodegenerative diseases: a review of upstream and
downstream antioxidant therapeutic options. Curr Neuro-
pharmacol 2009;7:65–74. Epub 2009/09/02.
73. Niedzielska E, Smaga I, Gawlik M, et al. Oxidative stress in
neurodegenerative diseases. Mol Neurobiol
2015;53:4094–125. Epub 2015/07/23.
74. Radi E, Formichi P, Battisti C, et al. Apoptosis and oxida-
tive stress in neurodegenerative diseases. J Alzheimers
Dis 2014;42(Suppl 3):S125–52. Epub 2014/07/25.
75. Chaudhuri TK, Paul S. Protein-misfolding diseases and
chaperone-based therapeutic approaches. FEBS J
2006;273:1331–49. Epub 2006/05/13.
76. Christians ES, MustafiSB, Benjamin IJ. Chaperones and
cardiac misfolding protein diseases. Curr Protein Pept Sci
2014;15:189–204. Epub 2014/04/04.
77. Cohen FE, Kelly JW. Therapeutic approaches to protein-
misfolding diseases. Nature 2003;426:905–9. Epub 2003/
12/20.
78. Denny RA, Gavrin LK, Saiah E. Recent developments in tar-
geting protein misfolding diseases. Bioorg Med Chem
Lett 2013;23:1935–44. Epub 2013/03/05.
79. Bernier V, Lagace M, Bichet DG, et al. Pharmacological
chaperones: potential treatment for conformational dis-
eases. Trends Endocrinol Metab 2004;15:222–8. Epub
2004/06/30.
80. Soto C, Kascsak RJ, Saborio GP, et al. Reversion of prion
protein conformational changes by synthetic beta-sheet
breaker peptides. Lancet 2000;355:192–7. Epub 2000/02/
16.
81. Ryou C, Legname G, Peretz D, et al. Differential inhibition
of prion propagation by enantiomers of quinacrine. Lab
Invest 2003;83:837–43. Epub 2003/06/17.
82. Korth C, May BC, Cohen FE, et al. Acridine and phenothia-
zine derivatives as pharmacotherapeutics for prion dis-
ease. Proc Natl Acad Sci U S A 2001;98:9836–41. Epub
2001/08/16.
83. Sawkar AR, Cheng WC, Beutler E, et al. Chemical chaper-
ones increase the cellular activity of N370S beta-glucosi-
dase: a therapeutic strategy for Gaucher disease. Proc
Natl Acad Sci U S A 2002;99:15428–33. Epub 2002/11/16.
84. Cortez L, Sim V. The therapeutic potential of chemical
chaperones in protein folding diseases. Prion 2014;8:197–
202.
85. Singh R, Haque I, Ahmad F. Counteracting osmolyte tri-
methylamine N-oxide destabilizes proteins at pH below
its pKa: measurements of thermodynamic parameters of
proteins in the presence and absence of trimethylamine
N-oxide. J Biol Chem 2005;280:11035–42. Epub 2005/01/
18.
86. Morgan D. Immunotherapy for Alzheimer’s disease. J
Intern Med 2011;269:54–63. Epub 2010/12/17.
87. Karran E, Mercken M, De Strooper B. The amyloid cascade
hypothesis for Alzheimer’s disease: an appraisal for the
development of therapeutics. Nat Rev Drug Discov
2011;10:698–712. Epub 2011/08/20.
88. Lee EB, Leng LZ, Zhang B, et al. Targeting amyloid-beta
peptide (Abeta) oligomers by passive immunization with
a conformation-selective monoclonal antibody improves
learning and memory in Abeta precursor protein (APP)
transgenic mice. J Biol Chem 2006;281:4292–9. Epub
2005/12/20.
89. Janus C, Pearson J, McLaurin J, et al. A beta peptide
immunization reduces behavioural impairment and pla-
ques in a model of Alzheimer’s disease. Nature
2000;408:979–82. Epub 2001/01/05.
90. Dodel R, Neff F, Noelker C, et al. Intravenous immunoglo-
bulins as a treatment for Alzheimer’s disease: rationale
and current evidence. Drugs 2010;70:513–28. Epub 2010/
03/25.
91. Doody RS, Farlow M, Aisen PS. Phase 3 trials of solanezu-
mab and bapineuzumab for Alzheimer’s disease. N Engl J
Med 2014;370:1460. Epub 2014/04/11.
92. Salloway S, Sperling R, Brashear HR. Phase 3 trials of sola-
nezumab and bapineuzumab for Alzheimer’s disease. N
Engl J Med 2014;370:1460. Epub 2014/04/12.
93. Galzitskaya OV. Repeats are one of the main characteris-
tics of RNA-binding proteins with prion-like domains. Mol
Biosyst 2015;11:2210–8. Epub 2015/05/30.
94. Sigurdsson EM, Brown DR, Daniels M, et al. Immunization
delays the onset of prion disease in mice. Am J Pathol
2002;161:13–7. Epub 2002/07/11.
95. Aguzzi A, Rajendran L. The transcellular spread of cyto-
solic amyloids, prions, and prionoids. Neuron
2009;64:783–90. Epub 2010/01/13.
96. Imbimbo BP. Toxicity of beta-amyloid vaccination in
patients with Alzheimer’s disease. Ann Neurol
2002;51:794. Epub 2002/07/12.
INTERNATIONAL JOURNAL OF NEUROSCIENCE 1055
97. O’Nuallain B, Wetzel R. Conformational Abs recognizing a
generic amyloid fibril epitope. Proc Natl Acad Sci U S A
2002;99:1485–90. Epub 2002/01/31.
98. Solomon B. Clinical immunologic approaches for the
treatment of Alzheimer’s disease. Expert Opin Investig
Drugs 2007;16:819–28. Epub 2007/05/16.
99. Bieschke J, Herbst M, Wiglenda T, et al. Small-molecule
conversion of toxic oligomers to nontoxic beta-sheet-rich
amyloid fibrils. Nat Chem Biol 2012;8:93–101. Epub 2011/
11/22.
100. O’Connor DM, Boulis NM. Gene therapy for neurodegen-
erative diseases. Trends Mol Med 2015;21:504–12. Epub
2015/07/01.
101. Nanou A, Azzouz M. Gene therapy for neurodegenerative
diseases based on lentiviral vectors. Prog Brain Res
2009;175:187–200. Epub 2009/08/08.
102. Koutsilieri E, Rethwilm A, Scheller C. The therapeutic
potential of siRNA in gene therapy of neurodegenerative
disorders. J Neural Transm Suppl 2007:43–9. Epub 2007/
11/07.
103. Seyhan AA. RNAi. A potential new class of therapeutic for
human genetic disease. Hum Genet 2011;130:583–605.
Epub 2011/05/04.
104. Kumar A, Narayanan K, Chaudhary RK, et al. Current per-
spective of stem cell therapy in neurodegenerative and
metabolic diseases. Mol Neurobiol 2016. Epub 2016/11/
07.
105. Lunn JS, Sakowski SA, Hur J, Feldman EL. Stem cell tech-
nology for neurodegenerative diseases. Ann Neurol
2011;70:353–61. Epub 2011/09/10.
106. Lindvall O, Kokaia Z. Stem cells for the treatment of neu-
rological disorders. Nature 2006;441:1094–6. Epub 2006/
07/01.
107. Shin JW, Lee JK, Lee JE, et al. Combined effects of
hematopoietic progenitor cell mobilization from bone
marrow by granulocyte colony stimulating factor and
AMD3100 and chemotaxis into the brain using stromal
cell-derived factor-1alpha in an Alzheimer’s disease
mouse model. Stem Cells 2011;29:1075–89. Epub 2011/
05/25.
108. Singh C, Liu L, Wang JM, et al. Allopregnanolone restores
hippocampal-dependent learning and memory and neu-
ral progenitor survival in aging 3xTgAD and nonTg mice.
Neurobiol Aging 2012;33:1493–506. Epub 2011/08/02.
109. Bae JS, Jin HK, Lee JK, et al. Bone marrow-derived mesen-
chymal stem cells contribute to the reduction of amyloid-
beta deposits and the improvement of synaptic transmis-
sion in a mouse model of pre-dementia Alzheimer’sdisease.
Curr Alzheimer Res 2013;10:524–31. Epub 2012/10/06.
110. Yang H, Xie Z, Wei L, et al. Human umbilical cord mesen-
chymal stem cell-derived neuron-like cells rescue mem-
ory deficits and reduce amyloid-beta deposition in an
AbetaPP/PS1 transgenic mouse model. Stem Cell Res
Ther 2013;4:76. Epub 2013/07/06.
111. Nishino H, Hida H, Takei N, et al. Mesencephalic neural
stem (progenitor) cells develop to dopaminergic neurons
more strongly in dopamine-depleted striatum than in
intact striatum. Exp Neurol 2000;164:209–14. Epub 2000/
07/06.
112. Shen Y, Huang J, Liu L, et al. A compendium of prepara-
tion and application of stem cells in Parkinson’s disease:
current status and future prospects. Front Aging Neuro-
science 2016;8:117. Epub 2016/06/16.
113. Barker RA, Parmar M, Kirkeby A, et al. Are stem cell-based
therapies for Parkinson’s disease ready for the clinic in
2016? J Parkinsons Dis 2016;6:57–63. Epub 2016/03/24.
114. Zhu B, Caldwell M, Song B. Development of stem cell-
based therapies for Parkinson’s disease. Int J Neurosci
2016;126:955–62. Epub 2016/01/30.
115. Kefalopoulou Z, Politis M, Piccini P, et al. Long-term clini-
cal outcome of fetal cell transplantation for Parkinson dis-
ease: two case reports. JAMA Neurol 2014;71:83–7. Epub
2013/11/13.
116. Xu X, Huang J, Li J, et al. Induced pluripotent stem cells
and Parkinson’s disease: modelling and treatment. Cell
Prolif 2016;49:14–26. Epub 2016/01/11.
117. Grealish S, Diguet E, Kirkeby A, et al. Human ESC-derived
dopamine neurons show similar preclinical efficacy and
potency to fetal neurons when grafted in a rat model of
Parkinson’s disease. Cell Stem Cell 2014;15:653–65. Epub
2014/12/18.
118. Muramatsu S, Okuno T, Suzuki Y, et al. Multitracer assess-
ment of dopamine function after transplantation of
embryonic stem cell-derived neural stem cells in a pri-
mate model of Parkinson’s disease. Synapse 2009;63:541–
8. Epub 2009/03/03.
119. Kerkis I, Haddad MS, Valverde CW, et al. Neural and mes-
enchymal stem cells in animal models of Huntington’s
disease: past experiences and future challenges. Stem
Cell Res Ther 2015;6:232. Epub 2015/12/17.
120. Precious SV, Rosser AE. Producing striatal phenotypes for
transplantation in Huntington’s disease. Exp Biol Med
(Maywood) 2012;237:343–51. Epub 2012/04/12.
121. Fink KD, Deng P, Torrest A, et al. Developing stem cell
therapies for juvenile and adult-onset Huntington’s dis-
ease. Regen Med 2015;10:623–46. Epub 2015/08/04.
122. Delli Carri A, Onorati M, Lelos MJ, et al. Developmentally
coordinated extrinsic signals drive human pluripotent
stem cell differentiation toward authentic DARPP-32C
medium-sized spiny neurons. Development
2013;140:301–12. Epub 2012/12/20.
123. Mu S, Wang J, Zhou G, et al. Transplantation of induced
pluripotent stem cells improves functional recovery in
Huntington’s disease rat model. PLoS One 2014;9:
e101185. Epub 2014/07/24.
124. Moura MC, Novaes MR, Zago YS, et al. Efficacy of stem cell
therapy in amyotrophic lateral sclerosis: a systematic
review and meta-analysis. J Clin Med Res 2016;8:317–24.
Epub 2016/03/18.
125. Kumar V, Islam A, Hassan MI, et al. Therapeutic progress in
amyotrophic lateral sclerosis-beginning to learning. Eur J
Med Chem 2016;121:903–17. Epub 2016/07/04.
126. Atassi N, Beghi E, Blanquer M, et al. Intraspinal stem cell
transplantation for amyotrophic lateral sclerosis: ready for
efficacy clinical trials? Cytotherapy 2016;18:1471–5. Epub
2016/11/05.
127. Chen KS, Sakowski SA, Feldman EL. Intraspinal stem cell
transplantation for amyotrophic lateral sclerosis. Ann
Neurol 2016;79:342–53. Epub 2015/12/24.
128. Thomsen GM, Gowing G, Svendsen S, et al. The past, pres-
ent and future of stem cell clinical trials for ALS. Exp Neu-
rol 2014;262 Pt B:127–37. Epub 2014/03/13.
1056 N. SAMI ET AL.
129. Dimos JT, Rodolfa KT, Niakan KK, et al. Induced pluripo-
tent stem cells generated from patients with ALS can be
differentiated into motor neurons. Science
2008;321:1218–21. Epub 2008/08/02.
130. Karussis D, Karageorgiou C, Vaknin-Dembinsky A, et al.
Safety and immunological effects of mesenchymal stem
cell transplantation in patients with multiple sclerosis and
amyotrophic lateral sclerosis. Arch Neurol 2010;67:1187–
94. Epub 2010/10/13.
131. Selivanova OV, Suvorina MY, Surin AK, et al. Insulin and
lispro insulin: what is common and different in their
behavior? Curr Protein Pept Sci 2016. Epub 2016/05/27.
132. Bobylev AG, Galzitskaya OV, Fadeev RS, et al. Smooth
muscle titin forms in vitro amyloid aggregates. Biosci Rep
2016;36. Epub 2016/04/30.
133. Dovidchenko NV, Glyakina AV, Selivanova OM, et al. One
of the possible mechanisms of amyloid fibrils formation
based on the sizes of primary and secondary folding
nuclei of Abeta40 and Abeta42. J Struct Biol
2016;194:404–14. Epub 2016/03/27.
134. Iwatsubo T. Aggregation of alpha-synuclein in the patho-
genesis of Parkinson’s disease. J Neurol 2003;250 (Suppl
3):III11–4. Epub 2003/10/28.
135. Lukas J, Scalia S, Eichler S, Pockrandt AM, et al. Functional
and clinical consequences of novel alpha-galactosidase a
mutations in Fabry disease. Hum Mutat 2016;37:43–51.
Epub 2015/09/30.
136. Cohen SI, Linse S, Luheshi LM, et al. Proliferation of amy-
loid-beta42 aggregates occurs through a secondary
nucleation mechanism. Proc Natl Acad Sci U S A
2013;110:9758–63. Epub 2013/05/25.
137. Holton JL, Ghiso J, Lashley T, et al. Regional distribution of
amyloid-Bri deposition and its association with neurofi-
brillary degeneration in familial British dementia. Am J
Pathol 2001;158:515–26. Epub 2001/02/13.
138. Holton JL, Lashley T, Ghiso J, et al. Familial Danish demen-
tia: a novel form of cerebral amyloidosis associated with
deposition of both amyloid-Dan and amyloid-beta. J Neu-
ropathol Exp Neurol 2002;61:254–67. Epub 2002/03/16.
139. Kanazawa I. Molecular pathology of dentatorubral-pallid-
oluysian atrophy. Philos Trans R Soc Lond B Biol Sci
1999;354:1069–74. Epub 1999/08/06.
140. Bowling AC, Barkowski EE, McKenna-Yasek D, et al. Super-
oxide dismutase concentration and activity in familial
amyotrophic lateral sclerosis. J Neurochem 1995;64:2366–
9. Epub 1995/05/01.
141. Couthouis J, Hart MP, Shorter J, et al. A yeast functional
screen predicts new candidate ALS disease genes. Proc
Natl Acad Sci U S A 2011;108:20881–90. Epub 2011/11/09.
142. Neumann M, Sampathu DM, Kwong LK, et al. Ubiquiti-
nated TDP-43 in frontotemporal lobar degeneration and
amyotrophic lateral sclerosis. Science 2006;314:130–3.
Epub 2006/10/07.
INTERNATIONAL JOURNAL OF NEUROSCIENCE 1057
