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European Journal of Pharmacology
journal homepage: www.elsevier.com/locate/ejphar
Full length article
Als and Ftd: Insights into the disease mechanisms and therapeutic targets
Rajka M. Liscic
MD, PhD, Ass. Professor, EUREGIO KLINIK Albert-Schweitzer Straße GmbH, Nordhorn, Germany and Department of Anatomy and Neuroscience, School of Medicine,
University of Osijek, Croatia
ARTICLE INFO
Keywords:
ALS
Dementia
FTD
Genetics
Motor neuron disease
TDP-43
Riluzole
Stem cells
ABSTRACT
Amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD) are neurodegenerative dis-
orders, related by signs of deteriorating motor and cognitive functions, and short survival. The causes are still
largely unknown and no effective treatment currently exists. It has been shown that FTLD may coexist with ALS.
The overlap between ALS and frontotemporal dementia (FTD), the clinical syndrome associated with FTLD,
occurs at clinical, genetic, and pathological levels. The hallmark proteins of the pathognomonic inclusions are
SOD-1, TDP-43 or FUS, rarely the disease is caused by mutations in the respective genes. Frontotemporal lobar
degenerations (FTLD) is genetically, neuropathologically and clinically heterogeneous and may present with
behavioural, language and occasionally motor disorder, respectively. Almost all cases of ALS, as well as tau-
negative FTLD share a common neuropathology, neuronal and glial inclusion bodies containing abnormal TDP-
43 protein, collectively called TDP-43 proteinopathy. Recent discoveries in genetics (e.g. C9orf72 hexanucleo-
tide expansion) and the subsequent neuropathological characterization have revealed remarkable overlap be-
tween ALS and FTLD-TDP indicating common pathways in pathogenesis. For ALS, an anti-glutamate agent ri-
luzole may be offered to slow disease progression (Level A), and a promising molecule, arimoclomol, is currently
in clinical trials. Other compounds, however, are being trailed and some have shown encouraging results. As new
therapeutic approaches continue to emerge by targeting SOD1, TDP-43, or GRN, we present some advances that
are being made in our understanding of the molecular mechanisms of these diseases, which together with gene
and stem cell therapies may translate into new treatment options.
1. Introduction
Amyotrophic lateral sclerosis (ALS) and frontotemporal dementia
(FTD) are related clinical phenotypes, which are characterized by de-
cline in motor and cognitive functions, and short survival. ALS is the
most common adult-onset motor neuron disease, characterized by the
progressive, irreversible motor neuron loss leading to denervation
atrophy of muscles and death by respiratory failure (Brookset al.,
2000). Both diseases are invariably fatal after only a few years (Brooks
et al., 2000). The causes of the more frequent sporadic forms remain
unknown and no effective treatment currently exists. However, an anti-
glutamate agent Riluzole has shown modest benefit and is the only drug,
so far, to receive US Food and Drug Administration (FDA) approval for
treatment of ALS (Miller et al., 1999). Also a Phase II/III randomised,
placebo-controlled trial of arimoclomol (BRX-345) in familial ALS with
SOD-1 mutation is underway (NCT00706147; www.ClinicalTrials.gov).
Arimoclomol, is a hydroxylamine derivative, a group of compounds
which have unique properties as co-inducers of heat shock protein ex-
pression, but only under conditions of cellular stress which is involved
in the ethiopathogenesis of multiple neurodegenerative diseases
including ALS (Kalmar et al., 2014). Treatment with arimoclomol has
been reported to improve survival and muscle function in different
mouse models of motor neuron disease including ALS and in mutant
superoxide dismutase 1 (SOD1) mice.
The small molecule arimoclomol may reduce the levels of protein
aggregates in motor nerves, a possible cause of ALS, by boosting ex-
pression of the heat shock proteins Hsp 70 and Hsp 90 which help
newly synthesised proteins to properly fold (www.alstdi.org;(Scotter
et al., 2015). Other compounds, including ceftriaxone and dexprami-
pexole, have been promoted and show encouraging results at phase II
clinical trials.
Ceftriaxone, belongs to a third generation of cafalosporine anti-
biotics, which can penetrate the blood brain barrier (BBB) and enter the
CNS. In addition to bactericidal action, ceftriaxone has been found in
various animal models to exert neuroprotective action caused by in-
creased expression of the astrocytic glutamate transporter, EAAT2 in
humans and GLT1 glutamate transporter in rodents. Glutamate trans-
porter EAAT2 increases the clearance of synaptic glutamate and pro-
tects neurons from glutamate-mediated excitotoxicity which is thought
to be a factor in their pathogenesis of ALS (Jagadapillai et al., 2014). In
http://dx.doi.org/10.1016/j.ejphar.2017.10.012
Received 27 October 2016; Received in revised form 6 October 2017; Accepted 9 October 2017
E-mail address: rajka.liscic@gmail.com.
European Journal of Pharmacology xxx (xxxx) xxx–xxx
0014-2999/ © 2017 Published by Elsevier B.V.
Please cite this article as: Liscic, R.M., European Journal of Pharmacology (2017), http://dx.doi.org/10.1016/j.ejphar.2017.10.012
ALS animal models, as well as in human post-mortem tissue, decreased
expression of glutamate transporter EAAT2 has been demonstrated.
Dexpramipexole is the enantiomer of pramipexole that is sig-
nificantly less effective dopamine receptor agonist but shows better
neuroprotective action. Dexpramipexole has been shown to inhibit the
opening of the mitochondrial permeability transition pore (PTP), im-
proving mitochondrial function and conferring significant protection to
neurons exposed to free radicals under cellular stress (Vieira et al.,
2014).
Unfortunately, neither of these compounds showed efficacy at stage
III clinical trials (Cudkowicz et al., 2014, 2013), most likely due to
already well-established disease. Stem cell therapies are emerging as
potential disease modulating therapies in autoimmune diseases e.g.
rheumatoid arthritis, multiple sclerosis, and lupus (Mazzini et al.,
2010). Preclinical studies have shown that neurotrophic growth factors
(NTFs) extend the survival of motor neurons in ALS. Recently, an Israeli
research group developed a culture-based method for inducing me-
senchymal stem cells (MSCs) to secrete neurotrophic growth factors
(NTFs). These MSC-NTF cells have been shown to be protective in an-
imal models of neurodegenerative diseases. They successfully ad-
ministered autologous MSC-NTF cells, derived from bone marrow
samples given by participants (26 ALS patients) in the trial, via in-
trathecal (i.t) or intramuscular (i.m.) administration which proved to be
safe and provided indications of possible clinical benefits. These ex-
periments are to be tested in upcoming clinical trials (Petrou et al.,
2016). This study showed that implanting stem cells that produce
neurotrophic factors (MSC-NTF) into either muscle or the intrathecal
space, or both, were shown to be safe and associated with only mild
adverse effects, principally headache and fever. This is the first study in
which stem cells that have been modified to secrete neurotrophic fac-
tors have been implemented in patients with ALS. These results, how-
ever, should be treated with caution, since the study included relatively
small group of patients and the trial did not include a placebo com-
parator.
Immunological therapies originally proved more promising, with a
Phase III antibody-Nogo study. The Nogo A is one of the three isoforms
of the Nogo protein that acts as a neurite outgrowth inhibitor of the
Nogo protein, encoded by the RTN4 gene (Pernet and Schwab, 2012).
However, although the study has been completed (NCT00406016,
www.ClinicalTrials.gov), no results have been published. For more on
clinical trials, please refer to www.ClinicalTrials.gov.
In FTD, which typically presents with either behavioural abnorm-
alities or language dysfunction, a considerable number of patients also
develop muscle weakness and wasting that is typical for ALS (Strong,
2008; Strong et al., 2009) or, vice versa, ALS patients may develop
impaired executive dysfunction and memory decline (Lomen-Hoerth
et al., 2002; Lomen-Hoerth et al., 2003). The presence of fronto-
temporal impairment in ALS predicts a shorter survival time (Hodges
et al., 2003) and behavioural and functional impairment may decline
independently of motor function (De Silva et al., 2015; Rohrer et al.,
2015).
With regard to treatments for FTD, a lot of symptomatic treatments
have been reported so far. Open-label studies of anticholinesterase
medicines have been negative and, in some cases they may even ex-
acerbate behavioural symptoms (Devenney, Vucic, Hodges, and
Kiernan, 2015). Similarly, a memantine study showed no effective
treatment in a recent randomized placebo controlled trial (Boxer et al.,
2012). The selective serotonin reuptake inhibitors and antipsychotic
therapies are generally considered helpful in the management of mood
and behavioural features in individual patients despite lack of evidence
(Devenney et al., 2015). Tauopathy, however, has been a focus for re-
search and the development of potential disease-modifying treatments
(Devenney et al., 2015). According to the latest study on tau-transgenic
mice, methylene blue substance, a drug in Phase III clinical trials stops
decline in its tracks- but only when given at the earliest stages
(Hochgrafe et al., 2015). This TRx-237-007 Phase 3 clinical trial
conducted in 220 subjects with bvFTD was stopped, as it failed to reach
its co-primary endpoints (TauRx Therapeutics Ltd. Sep 2016 conference
news; company press release).
The incidence of ALS in Europe is 2.16 per 100,000 (Logroscino
et al., 2010), while for FTD the incidence is 3.5 per 100,000 (Mercy
et al., 2008). Here we present a current understanding of molecular
causes of ALS and FTLD, in order to better understand pathogenetic
mechanisms of both diseases as new design for clinical trials emerges in
patients with ALS and FTD.
2. Genetics
A growing number of ALS-causing genes have been identified re-
cently. These are now under investigation as these may shed some light
on pathogenesis. Four major ALS-associated genes are: superoxide dis-
mutase 1 (SOD1), the first genetic cause to be identified, TAR DNA-
binding protein (TARDBP), fusion in malignant liposarcoma/
translocation in liposarcoma (FUS/TLS), and the most common
chromosome 9 open reading frame 72 (C9orf72).
Identification of disease linked mutations in TDP-43 and FUS/TLS
highlight dysfunctions in RNA metabolism as a common pathogenic
pathway in both ALS and FTD. TDP-43 and FUS/TLS have similar
structures and are involved in several RNA processing steps. TDP-43
binds to more than 6000 RNA targets and acts as a transcriptional re-
pressor through its direct binding to DNA. It is involved in splicing,
microRNA biogenesis, RNA transport and translation, and stress granule
formation. However, FUS/TLS can bind to a single or double-stranded
DNA and RNA. FUS/TLS interacts with RNA polymerase II and pro-
motes or represses the transcription of distinct genes and affects
Fig. 1. Pathology in cases of frontotemporal lobar degeneration-motor neuron disease
(FTLD-ALS) with C9orf72 expansion. The figure shows ubiquitin-positive, TDP-43-nega-
tive neuronal cytoplasmic inclusions (arrows) in the granule cells of the cerebellum (p62
immunohistochemistry). Scale bars: 20 micrometres. Courtesy of N.J. Cairns, Washington
University in St. Louis, USA.
Fig. 2. Pathology in cases of frontotemporal lobar degeneration-motor neuron disease
(FTLD-ALS) with C9orf72 expansion. The figure shows the cerebellar inclusions are la-
belled with anti-dipeptide repeat antibodies (poly-GA immunohistochemistry). Scale bars:
20 micrometres. Courtesy of N.J. Cairns, Washington University in St. Louis, USA.
R.M. Liscic European Journal of Pharmacology xxx (xxxx) xxx–xxx
2
splicing. Both, TDP-43 and FUS/TLS can modify the function of stress
granules and regulate synaptic function. When nuclear TDP is depleted,
it affects not only the expression of TDP-43, but also FUS/TLS, glial
transporter EAAT2, amyloid-beta precursor protein, presenilin, hun-
tingtin, multiple ataxins, alpha-synuclein, and progranulin. The most
affected molecular species is pre-mRNA (Ling et al., 2013).
In addition to neuronal inclusion bodies, both TDP-43 and FUS/TLS
aggregates may be found in glial cells. Another mutual characteristics of
ALS/FTP is a reactive gliosis (Radford et al., 2015). Reactive gliosis is
an unspecific response to noxious stimuli within brain and is char-
acterized by microglial proliferation and astrocytic hypertrophy. ALS-
FTP-induced reactive gliosis is the most prominent in the brain areas
showing neuronal loss and inclusion pathology. The pathologic function
of glia can further contribute to neurodegeneration in ALS/FTP by re-
leasing glia-derived neurotoxic compounds and by reducing the clear-
ance potential of glia. In addition to decreased phagocytic activity by
reactive glial cells, the reduced vascular and glymphatic flow which is
controlled by glia participates to disease spreading and progression (Ng
et al., 2015).
In 2011, the discovery of the hexanucleotide repeat expansion in the
C9orf72 gene was revealed as the most frequent genetic cause of both
ALS and FTD (DeJesus-Hernandez et al., 2011)(Renton et al., 2011). An
expanded hexanucleotide, G
4
C
2,
repeat in C9orf72, is pathogenic at
greater than 30 repeats (Fratta et al., 2015), with most patients having
expansions > 500 repeats. The characteristic pathological findings in
both ALS and FTLD are focal neuronal loss and gliosis and neuronal
cytoplasmic inclusion bodies containing TDP-43. Of the TDP-43 pro-
teinopathies, C9orf72 mutations are unique in that many inclusion
bodies also contain dipeptide repeat (DPR) proteins. Possible molecular
mechanisms of neurodegeneration include loss or gain in function of
the C9orf72 protein (Mizielinska et al., 2014; Rohrer et al., 2015). Loss
of protein function reflects reduced levels of C9orf72 in brain and in
vitro studies reveal a role for C9orf72 protein in endosomal and au-
tophagic pathways (Mizielinska et al., 2014). A toxic gain of function is
supported by the presence of both repeat RNA and protein aggregates in
post-mortem brain. Repeat RNA aggregates, or RNA foci, have been
shown to sequester proteins involved in RNA splicing, editing, nuclear
export, and nuclear function. An alternative-RNA-mediated mechanism
to RNA binding protein is associated with non-TGA (RAN) translation
which produces aberrant peptides or dipeptide polymers that form a
proportion of inclusion bodies in brain tissue (Zu et al., 2011). In
combating gain-of-function toxicity, oligonucleotides targeting C9orf72
show some success (Mizielinska and Isaacs, 2014).
Oligonucleotide-based antisense techniques represent to date one of
the more successful approaches to achieving suppression or elimination
of a genetic message. Classes of antisense oligonucleotide therapeutics
can be divided into: RNase-H-dependent, exon skipping antisense oli-
gonucleotides, siRNAs, anti-miRNA and miRNA mimics. RNase H-de-
pendent and exon skipping antisense nucleotides are single stranded,
chemically modified oligonucleotides. RNase-H-dependent oligonu-
cleotides bind to mRNA and reduce the gene expression by RNase-H
mediated cleavage of the target RNA and by inhibition of translation by
steric blockade of ribosomes, whereas exon skipping target intro-exon
junctions or splicing-regulatory elements. siRNA are small 21–23 nu-
cleotide long chemically modified with an antisense strand that is
complementary to a sequence anywhere in the target RNA. Anti-mi-Rs
and miRNA mimics either antagonise or mimics the endogenous
miRNA, but less efficiently than si RNAs. Oligonucleotides targeting
C9orf72 belong to RNase-H-dependent antisense nucleotides (Rosen
et al., 1993).
Three major ALS-associated genes, SOD1, which encodes Cu/Zn
superoxide dismutase-1 (Rosen et al., 1993), TARDBP, and FUS/TLS
have been identified with a growing number of ALS-causing genes.
These genes are now under investigation as providing promise for in-
creased understanding of pathogenesis of the disease (Liscic and
Breljak, 2011). Other genes, including angiogenin (ANG), the vesicle-
associated membrane protein-associated protein B (VAPB), senataxin
(SETX), and dynactin gene have been also identified in ALS patients.
Mutations in the FUS/TLS gene, located on chromosome 16, have been
identified as a causal gene for ~4% of FALS (~0.4% of all ALS)
(Kwiatkowski et al., 2009; Vance et al., 2009) and FTLD (Van
Langenhove et al., 2010). As with TDP-43, FUS is a predominantly
nuclear protein that is expressed at low levels in the cytoplasm (Lagier-
Tourenne and Cleveland, 2009). Although the phenotype associated
with FUS mutation is variable, most patients predominantly demon-
strate loss of lower motor neurons and short disease survival. Mutations
in the SOD1 were first described in 1993 (Rosen et al., 1993). Since then
more than 120 different SOD1 mutations have been identified and
claimed to be responsible for 20% of FALS cases (Liscic and Breljak,
2011). In 2008, Gitcho and colleagues (Gitcho et al., 2008) and
Sreedharan and colleagues (Sreedharan et al., 2008) independently
reported pathogenic mutations in the TARDBP gene located on chro-
mosome 1 encoding TAR DNA-binding protein 43 (TDP-43), which
cause several neurodegenerative diseases such as FALS, sporadic ALS,
and FTLD. Their findings support a direct role of TARDBP mutations in
neurodegeneration. TDP-43 is a 414-amino acid ubiquitously expressed
nuclear protein, which contains two highly conserved RNA-recognition
motifs (RRM1 and RRM2), a nuclear localisation signal at the N-ter-
minus, and a glycine-rich region mediating protein-protein interactions
at the C-terminus (Lagier-Tourenne and Cleveland, 2009). Pathological
C-terminal TDP-43 fragments of 25 kDa are ubiquitinated, hyperpho-
sphorylated and accumulated as cellular inclusions in neurons and glial
cells (Neumann et al., 2006). To explore the link between mutations in
TARDBP and the spectrum of TDP-43 proteinopathies TDP-43 mutant
transgenic mice models with clinical features of ALS and FTD have been
developed, however, with varying results (Wegorzewska et al., 2009;
Wils et al., 2010). Although it may be impossible to model accurately
one clinical feature of a human neurodegenerative disease in mice,
mouse models are useful in that they shed light on pathogenic me-
chanisms causing cell death and he clinical phenotypes associated with
both ALS and FTD; however, mouse models have had only limited
success in recapitulating the neuropathology of TDP-43 proteinopathy
(Ittner et al., 2015). The identification of SOD-1 mutations in FALS and
MAPT mutations in FTDP-17 (Rosen et al., 1993) prompted the gen-
eration of several mouse TARDBP mutants (Igaz et al., 2011). However,
none of these models is perfect. Mutations in GRN also result in TDP-43
neuropathology in humans, but knockout mice show little pathologi-
cally phosphorylated TDP-43 (Wils et al., 2012), thus indicating that
the link between gene defect and pathology is complex. Recently, the
first (Hukema et al., 2014) repeat-expansion mouse model and
knockout mice was reported (Panda et al., 2013), but without a human-
related pathologic phenotype. The high prevalence of C9orf72 muta-
tions in familial FTD-ALS suggests that accurate mouse models of this
mutation will be necessary to facilitate drug discovery and develop-
ment.
3. Neuropathology of ALS and FTLD (frontotemporal lobar
degeneration)
Clinically and neuropathologically, ALS and FTD or its pathological
substrate called frontotemporal lobar degeneration (FTLD) may be seen
as two ends of a spectrum (Cairns et al., 2007). For example, TDP-43
proteinopathy characterizes most sporadic cases of both ALS and FTLD.
However, the significance of TDP-43-immunoreactive inclusion bodies
in the pathogenesis of ALS-FTLD remains enigmatic (Buratti, 2015).
The neuropathology of ALS is characterized mainly by the abnormal
accumulation of insoluble proteins as inclusion bodies in the cytoplasm
of degenerating motor neurons (Lowe, 1994; Neumann et al., 2006).
Until recently, the specific biochemical composition of these neuronal
cytoplasmic inclusions (NCIs) was unknown, except that the abnormal
protein was ubiquitinated. These ubiquitin-immunoreactive (ub-ir)
NCIs are most common in surviving lower motor neurons and most
R.M. Liscic European Journal of Pharmacology xxx (xxxx) xxx–xxx
3
often appear as either filamentous skeins or compact round bodies
(Lowe, 1994).
ALS is accompanied by a wide range of neuropathological features
in which both cortical (upper motor neuron) and either brainstem
motor neurons or anterior horn cells (lower motor neuron) are involved
with the signature lesion: abnormal accumulation of aggregated pro-
teins in cytoplasm of degenerating motor neurons (Wong et al., 1995).
Until recently, the pathological proteins in these inclusion bodies of ALS
and FTL with ubiquitin-immunoreactive inclusions were largely. TDP-
43 was identified as the most frequent protein in the inclusions of both
ALS an FTLD (Liscic, 2015; Liscic, Grinberg, Zidar, Gitcho, and Cairns,
2008). TDP-43 is normally found within the nucleus but under patho-
logical conditions, TDP-43 is translocated to the cytoplasm where ab-
normal inclusion bodies are formed. Although most inclusions are seen
within neurons they may also be found in glial cells. Biochemical
analysis of purified NCIs indicates that pathologic TDP-43 is ubiquiti-
nated, hyperphosphrylated, and accumulates as abnormal C-terminally
fragments of 25 kDa (Neumann et al., 2006). TFP-43 proteinopathy
now constitutes the most frequent molecular pathology of FTLD; about
half of cases contain abnormal tau, called the tauopathies, and a re-
sidual group of about 5 per cent of cases are characterized aby ab-
normal inclusion bodies containing FUS, collectively called the FUS
proteinopathies. But it is not clear weather aggregation of TDP-43 is a
primary event in ALS pathogenesis or whether it is a by-product of
another pathological process. Phosphorylated 43 kDa TAR DNA-
binding protein (pTDP-43) intraneuronal inclusions in ALS are found
within the motor cortex, brainstem motor nuclei, cranial nerve nuclei V,
VII, and X-XII, and in spinal cord motor neurons. In cases with a
C9orf72 hexanucleotide expansion there may be a more florid TDP-43
molecular pathology (Brettschneider et al., 2014). A unique feature of
C9orf72 cases is the presence of dipeptide repeat proteins in many in-
clusion bodies that are TDP-43 negative (Al-Sarraj et al., 2011), Figs. 1
and 2.
4. Innovative perspectives and conclusion
Most ALS and FTLD cases are progressive, relatively frequent,
neurodegenerative diseases without a known cause. In familial ALS
(FALS) many causative gene defects have been described (for an up-to-
date list see: http://alsod.iop.kcl.ac.uk/). The only drug currently li-
censed for the symptomatic ALS treatment today is an anti/glutamate
agent Riluzole. Also, immunological therapies proved promising, with a
Phase III Nogo Antibody study and an investigational agent arimoclomol
currently in clinical trials. However, the Nogo antibody study showed
no encouraging results.
Recently, new emerging results were presented with stem cell
therapies as potential disease modulating therapies. The bone marrow
cells were turned into stem cells that secrete neurotrophic factor (NTF).
By implanting mesenchymal stem cells (MSC) that produce neuro-
trophic factor (MSC-NTF) in patients with ALS into either muscle or the
intrathecal space, or both, the study showed to be safe and associated
with only mild adverse effects, principally headache and fever. This is
the first study in which stem cells that have been modified to secrete
neurotrophic factors have been tested in patients with ALS. These re-
sults, however, should be treated with caution since the study included
relatively small numbers of patients and the trial did not include a
placebo comparator.
Major discoveries, however, have been made in the recent past in
the genetics, biochemistry, and neuropathology of ALS and FTLD. The
C9orf72 hexanucleotide repeat expansion is the most common genetic
cause of both ALS and FTD; all of these cases display TDP-43.
Interestingly, multiple gene defects in C9orf72,TARDBP, and VCP all
produce TDP-43 proteinopathy with C9orf72 cases having unique pa-
thological features. Conversely, mutations in a single gene, MAPT,
produce a heterogeneous pathology, tauopathy, and mutations in FUS/
TLS are linked to FALS with FUS proteinopathy. The revised
classification of ALS and FTLD according to genetics and molecular
pathology is providing new insights into pathogenesis and potential
new targets for therapeutic intervention. Accompanying these ap-
proaches, gene (and eventually stem cell) therapies may provide some
relief to these, at present, incurable neurodegenerative diseases.
Acknowledgement
Figures were kindly provided by NJ Cairns, PhD, Washington
University School of Medicine, St. Louis, Missouri, U.S.A.
Disclosure
The author declares no competing conflict of interest.
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