REVIEW
published: 14 February 2018
doi: 10.3389/fgene.2018.00029
A Comprehensive Atlas of E3
Ubiquitin Ligase Mutations in
Neurological Disorders
Arlene J. George 1 , Yarely C. Hoffiz 1 , Antoinette J. Charles 1 , Ying Zhu 2 and
Angela M. Mabb 1*
1
Neuroscience Institute, Georgia State University, Atlanta, GA, United States, 2 Creative Media Industries Institute &
Department of Computer Science, Georgia State University, Atlanta, GA, United States
Edited by:
Amritha Jaishankar,
Rare Genomics Institute,
United States
Reviewed by:
Nelson L. S. Tang,
The Chinese University of Hong Kong,
Hong Kong
Musharraf Jelani,
Department of Genetic Medicine, King
Abdulaziz University, Saudi Arabia
*Correspondence:
Angela M. Mabb
amabb@gsu.edu
Specialty section:
This article was submitted to
Genetic Disorders,
a section of the journal
Frontiers in Genetics
Received: 01 September 2017
Accepted: 22 January 2018
Published: 14 February 2018
Citation:
George AJ, Hoffiz YC, Charles AJ,
Zhu Y and Mabb AM (2018) A
Comprehensive Atlas of E3 Ubiquitin
Ligase Mutations in Neurological
Disorders. Front. Genet. 9:29.
doi: 10.3389/fgene.2018.00029
Frontiers in Genetics | www.frontiersin.org
Protein ubiquitination is a posttranslational modification that plays an integral part
in mediating diverse cellular functions. The process of protein ubiquitination requires
an enzymatic cascade that consists of a ubiquitin activating enzyme (E1), ubiquitin
conjugating enzyme (E2) and an E3 ubiquitin ligase (E3). There are an estimated
600–700 E3 ligase genes representing ∼5% of the human genome. Not surprisingly,
mutations in E3 ligase genes have been observed in multiple neurological conditions.
We constructed a comprehensive atlas of disrupted E3 ligase genes in common (CND)
and rare neurological diseases (RND). Of the predicted and known human E3 ligase
genes, we found ∼13% were mutated in a neurological disorder with 83 total genes
representing 70 different types of neurological diseases. Of the E3 ligase genes identified,
51 were associated with an RND. Here, we provide an updated list of neurological
disorders associated with E3 ligase gene disruption. We further highlight research in
these neurological disorders and discuss the advanced technologies used to support
these findings.
Keywords: ubiquitin, neurological, rare diseases, angelman syndrome, transgenic
INTRODUCTION
Protein ubiquitination is a posttranslational modification that involves the covalent tethering of
a small 76 amino acid protein called ubiquitin to target proteins (Hershko and Ciechanover,
1998). Ubiquitination mediates many cellular functions, which include signal transduction and the
removal of proteins by the ubiquitin proteasome system (UPS) (Hershko, 1996). The initiation of
protein ubiquitination typically requires an ATP-dependent enzymatic cascade that is initiated with
the priming of a ubiquitin onto a ubiquitin activating enzyme (E1) and the transfer to a ubiquitin
conjugating enzyme (E2) (Komander and Rape, 2012; Zheng and Shabek, 2017). Ubiquitin is then
covalently attached to a lysine residue on the target protein by an E3 ubiquitin ligase (E3) and this
process can be repeated to create a series of ubiquitin chains (Hershko and Ciechanover, 1998).
Ubiquitin chains can take various forms in length and configuration. The fate of these chains leads
to multiple cellular functions, one of which provides a signal for the protein to undergo degradation
by the UPS (Swatek and Komander, 2016; Yau and Rape, 2016).
Although there are only 2 E1 and 30-50 E2 genes, there are over 600 human E3 ligase genes
whose diversity is accounted for by three different types of catalytic domains: Really Interesting
New Gene (RING), Homologous to E6-AP Carboxyl Terminus (HECT), or Ring-Between-Ring
(RBR) (Zheng and Shabek, 2017). While both RING and HECT E3 ligases transfer ubiquitin to a
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E3 Ligase Mutations in Neurological Disorders
apparatus, centrosome, nucleus, cytoskeleton and synapse
(Yamada et al., 2013). Indeed, disruptions in ubiquitin pathway
components have been identified in numerous human disorders
which include those related to generalized inflammation and
cancer (Hegde and Upadhya, 2011; Upadhyay et al., 2017).
Notably, ubiquitination mediates many forms of synaptic
plasticity, which ultimately affect learning and memory (Mabb
and Ehlers, 2010; Hegde et al., 2014). Below, we discuss how
advanced technologies in CNDs and RNDs have been used to
broaden the understanding of E3 ligases in neurological disease
and have allowed researchers to exploit avenues for effective
therapies. Although this review cannot encompass a thorough
analysis of each disorder, we will focus on the technologies that
were used to study E3 ligase disruptions in RNDs, highlighting
their importance in increasing our generalized understanding of
rare disease.
lysine residue on the substrate, RING E3s act as a platform to
allow direct transfer of ubiquitin from the E2 to the substrate
(Riley et al., 2013). HECT E3s on the other hand, contain a
catalytic cysteine residue that can form a thioester bond directly
with ubiquitin. The RBR acts as a hybrid protein of 2 domains,
RING and HECT, with each family having various domains
leading to the ubiquitination of numerous substrates (Marín
et al., 2004; Zheng and Shabek, 2017). Proteins that are part of
the RBR family have both a canonical RING domain as well as
a catalytic cysteine residue similar to the HECT domain (Riley
et al., 2013).
E3 ligases have been linked to neurological disorders that
include neurodegeneration, neurodevelopmental disorders, and
intellectual disability (Hegde and Upadhya, 2011; Upadhyay
et al., 2017), many of which have no known effective therapies.
Neurological disorders are a heterogeneous group of disorders
that result from the impairment of the central and peripheral
nervous system, affect 1 in 6 individuals, and contribute to
12% of total deaths worldwide (WHO, 2006). Rare neurological
disorders (RNDs) are a subtype of neurological diseases that
represent 50% of all rare diseases, affecting fewer than 200,000
people in the United States, and are often overlooked due to
lack of understanding their potential causative factors (Han
et al., 2014; Jiang et al., 2014; NCATS, 2016). Although
neurological disorders encompass a large array of genetic defects,
next-generation sequencing (NGS) has enabled researchers to
identify constituents of the ubiquitin pathway, namely E3
ligases, as causative factors for neurological disease (Krystal
and State, 2014; McCarroll et al., 2014; Brown and Meloche,
2016). We speculated that recent advances in NGS resulted
in a massive expansion of the list of E3 ligases mutated in
neurological disease. To test this, we performed an unbiased
manual database search of ∼660 predicted and known human
E3 ligase genes specifically mutated in neurological disease (Li
et al., 2008; Hou et al., 2012). Strikingly, we found ∼13% of
E3 ligase genes were mutated in a neurological disorder with
83 total genes representing 70 different types of neurological
diseases (Supplementary Tables 1, 2). Of the E3 ligase genes
identified, 19 were associated with a CND (Figures 1, 2 and
Supplementary Table 1), while 51 were associated with an RND
(Figures 3, 4 and Supplementary Table 2). Thus, understanding
how E3 ligase disruption is a causative factor for neurological
disease may contribute to a strategy for therapeutic interventions
for both CNDs and especially RNDs (Upadhyay et al., 2017).
The critical role of E3 ligases in neuropathology has
been well documented in CNDs and is the result of both
classic methodologies and innovative technologies that parsed
out the consequences of E3 ligase disruption. However, very
little is known about E3 ligase functions in RNDs such as
identification of E3 ligase substrates, their definitive mechanisms,
their long-term effects on a cellular and systematic level,
and how to ameliorate these effects (Mabb and Ehlers, 2010;
Atkin and Paulson, 2014). In the nervous system, E3 ligases
are an integral part of the ubiquitin proteasome pathway
involved in the turnover of proteins (Tai and Schuman,
2008; Mabb and Ehlers, 2010; Yamada et al., 2013). They
localize to multiple cellular regions, which include the Golgi
Frontiers in Genetics | www.frontiersin.org
E3 UBIQUITIN LIGASES AND COMMON
NEUROLOGICAL DISEASE
Parkinson Disease
Parkinson disease (PD) is one of the most well-studied
neurological diseases related to E3 ligase dysfunction. PD is
characterized by dystonia, rigidity, tremors, hyperreflexia,
bradykinesia, postural instability, substantia nigra gliosis and
dopamine depletion, and Lewy body dementia (Halliday et al.,
2014; Biundo et al., 2016). The prevalence of this disease occurs
in 0.3% of the general population in the United States and
0.1–0.2% in European countries with increasing rates that occur
with aging (Kowal et al., 2013; Tysnes and Storstein, 2017).
Genetic mutations in the E3 ligases LRSAM1, FBXO7 (PARK
15), and PARK2 (Figure 1 and Supplementary Table 1) have
been identified in Parkinson disease (Wu et al., 2005; Choi et al.,
2008; Lohmann et al., 2015; Aerts et al., 2016). PARKIN/PARK2,
belongs to the RBR family of E3 ligases, and mutations in this
gene occurs in 50% of familial cases and 10–20% in sporadic
cases with high penetrance in early-onset PD (Lill, 2016; Zhang
et al., 2016).
A series of advanced technologies have elucidated the
functional consequences of deletion and missense mutations
in the PARKIN gene (Wu et al., 2005; Choi et al., 2008) and
their use has increased the capacity for PD therapeutics (Hattori
et al., 1998; Kitada et al., 1998; Hedrich et al., 2001). For
example, proteomic profiling demonstrated PARKIN’s role in
mitochondrial autophagy (Narendra and Youle, 2011). These
findings were further supported by liquid chromatography–mass
spectrometry and ubiquitin Absolute Quantification of ubiquitin
(UB-AQUA) proteomics. UB-AQUA is a mass spectrometrybased method that uses internal standard peptides that are
isotopically labeled to quantify peptides from digested mono- and
poly-ubiquitinated chains attached on substrates (Kirkpatrick
et al., 2006; Phu et al., 2011). UB-AQUA was used to identify
and quantify subtypes of mitochondrial ubiquitin chain linkages.
Using this method, PTEN-induced putative kinase 1 (PINK1)
was found to phosphorylate PARKIN leading to its activation
and formation of canonical and non-canonical ubiquitin chains
on mitochondria, which were PARKIN-dependent (Ordureau
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E3 Ligase Mutations in Neurological Disorders
et al., 2014). This served as a feed-forward mechanism to
promote PARKIN recruitment and mitochondrial ubiquitination
in response to mitochondrial damage. Collectively, these findings
were critical to understanding potential causative factors leading
to PD pathogenesis (Ordureau et al., 2014).
The impairment of mitochondria in PD due to deletions
of mitochondrial DNA (mtDNA) leads to respiratory-chain
deficiencies especially in dopamine (DA) neurons of the
substantia nigra (Bender et al., 2006). To study the effects
of mtDNA deletions and other genetic mutations, conditional
knock-out or knock-in mouse models using CRE recombinase
and loxP sites were used (Soriano, 1999). The CRE-loxP system
allows for conditional loss-of-function or gain-of-function
studies in specific tissues and circumvents early life lethality
and unwanted phenotypes in later stages of life by controlling
when genes are expressed temporally and spatially (Sauer, 1998).
A MitoPark reporter mouse line was created first by inserting
a loxP-flanked stop-cassette upstream of the mitochondrial
targeting presequence lox and yellow fluorescent protein (YFP)
transgene to target it to the mitochondrial matrix. The presence
of the stop cassette limits YFP expression in specific cells and is
only expressed when the stop cassette is excised out with CRE.
Using the MitoPark mouse model, the consequences of
respiratory chain dysfunction on the properties of mitochondria
and DA neurons were examined after DA neuron-specific
knockout of the mitochondrial transcription factor A (TFAM)
(Sterky et al., 2011). In order to study the DA neurons,
ROSA26+/SmY mice were crossed with dopamine transporter
(DAT)-CRE mice that express CRE under a DA transporter
locus, so the offspring from these parents express YFP precisely
in the mitochondria of DA neurons in the midbrain (Sterky
et al., 2011). Using this model, Sterky et al. demonstrated
increased fragmented and aggregated mitochondria in aged
PARKIN knockout mice (Sterky et al., 2011). Specifically, striatal
DA neurons displayed a reduction in mitochondria and tyrosine
hydroxylase density. Surprisingly, PARKIN knockout MitoPark
mice presented no difference in morphology or number of
mitochondria with or without PARKIN. There was also no
indication of PARKIN recruitment to defective mitochondria
suggesting PARKIN did not have an effect on the progression of
neurodegeneration in PD (Sterky et al., 2011).
Although limitations exist in using the PD mouse model,
there have been advancements in studying the role of PARKIN
in PD in a pig model. Large animals such as pigs serve as great
models to study pathological phenotypes for human neurological
diseases due to their physiological similarity to humans (Prather
et al., 2013). Wang et al. successfully implemented the clustered
regularly interspaced short palindromic repeats (CRISPR)/Cas9
system into the Bama miniature pig genome to concurrently
target three distinct loci by co-injecting cas9 mRNA and
single-guide RNAs (sgRNA) which target PARKIN, DJ-1, and
PINK1 genes into pronuclear embryos (Wang et al., 2016).
Immunofluorescence, western blotting and reverse transcriptionpolymerase chain reaction (RT-PCR) confirmed a significant
reduction in expression of these genes compared to wild-type
with a low incidence of off-target mutations via whole-genome
FIGURE 1 | Common neurological disorders (CNDs) and E3 ligase gene
associations. Diagram of CNDs correlated with E3 ligase genes that are
mutated in specific disorders. Diseases shaded in blue indicate multiple genes
linked to that disorder. Genes highlighted in dark gray are shared between
several diseases. Figures were generated using Graphviz (www.graphviz.org).
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FIGURE 2 | Common neurological disorders (CNDs) and their associated E3 ligase domain type. CNDs that contain mutations in E3 ligase domains (blue). Diseases
such as schizophrenia and Alzheimer’s disease accompany mutations in different types of E3 ligases. Figures were generated using Graphviz (www.graphviz.org).
PD patients with specific PARKIN mutations that demonstrate
dysfunctional mitophagy, therapeutic interventions could be
targeted to prevent oxidative stress or promote regeneration of
these cells via stem cell technologies specifically to DA neurons
of the midbrain.
sequencing. Despite the drawbacks to using large animals as a
means of genetic modification, including the fact that it is a timeconsuming and expensive procedure due to lack of embryonic
stem cell (ESC) lines, the effective and specific biallelic knockouts of genes makes this a valuable tool to study neurological
disorders where other animal models have failed.
Along with studying large model organisms, the PD field
has also taken advantage of using patient-derived induced
pluripotent stem cells (iPSCs). IPSCs are a special type of stem
cell in which human somatic cells are engineered and genetically
altered to be differentiated into other types of cells in the body
such as neuronal, cardiac or hepatic via distinct transcription
factors (Bellin et al., 2012). IPSCs make an extraordinary model
for studying human diseases because they can reveal phenotypic
defects and are a renewable source. Chung et al. differentiated
PARKIN/PINK1 mutant and normal iPSC and ESC lines of
midbrain DA neurons such that all cell lines demonstrated
properties consistent with development of midbrain DA neurons
(Chung et al., 2016). Although PARKIN and PINK1-derived
iPSCs showed abnormal mitochondria (enlarged and enhanced
oxidative stress), they were not prone to cell death. When given
an oxidative stress inducer, carbonyl cyanide m-chlorophenyl
hydrazine (CCCP), PD iPSC cell lines were more susceptible to
cell death and displayed atypical neurotransmitter homeostasis
(Chung et al., 2016).
In summary, upon mitochondrial depolarization, PINK1
recruits PARKIN to the mitochondrial membrane and its
phosphorylation permits proteasome-dependent degradation of
damaged mitochondria and enhances cell survival by suppressing
apoptosis. Using whole exome genome sequencing to identify
Frontiers in Genetics | www.frontiersin.org
E3 UBIQUITIN LIGASES AND RARE
NEUROLOGICAL DISORDERS
Extensive examination of RNDs are difficult to accomplish due
to the small number of human populations that have RNDs;
however, the use of in vitro and in vivo models along with the
genomic tools described above have made it possible to identify
mutations of genes, particularly E3 ligases, and to recapitulate
mutations observed in RNDs.
Angelman Syndrome
Angelman syndrome (AS) is a neurodevelopmental disorder that
is one of the most well studied RNDs. Although specific
symptoms vary in individual cases, AS is characterized
by intellectual disability, developmental delay, distinct
behavioral patterns such as a happy demeanor with prolonged,
inappropriate laughter and smiling, speech impairment, seizures,
abnormal sleep patterns, and ataxia (Williams et al., 2006; Tan
and Bird, 2016). AS occurs in about one out of every 12,000
births (Steffenburg et al., 1996). Over 90% of AS cases are
caused by mutations in the E3 ligase, UBE3A or deletions in
the 15q11-13 maternal region containing UBE3A (Figure 3
and Supplementary Table 2; Kishino et al., 1997; Matsuura
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et al., 1997; Sutcliffe et al., 1997). Similar to UBE3A, mutations
in another E3 ligase, HERC2, also lead to AS-like phenotypes
(Puffenberger et al., 2012).
UBE3A encodes a HECT E3 ligase that is imprinted
specifically in neurons of the central nervous system. Imprinting
is established and maintained through expression of a long
noncoding RNA on the paternal allele called the UBE3A antisense
(UBE3A-ATS) transcript. As a result, only maternal UBE3A is
expressed in neurons (Albrecht et al., 1997; Rougeulle et al., 1998;
Runte et al., 2001, 2004; Yamasaki et al., 2003; Landers et al.,
2004). Epigenetic regulation of UBE3A is similarly conserved in
rodents, which has allowed researchers to generate AS murine
models to study this disorder (Jiang et al., 1998). Using genetic
engineering techniques, mouse models for AS were created to
generate a viable maternally inherited Ube3a null mutation and
a conditional reinstatement model has been created to restore
the Ube3a null mutation during development (Jiang et al.,
1998, 2010; Miura et al., 2002; Silva-Santos et al., 2015). AS
mice display many AS-relevant phenotypes which include motor
deficits, seizure susceptibility, learning impairments, and altered
sleep homeostasis (Jiang et al., 1998, 2010; Miura et al., 2002;
Cheron et al., 2005; Colas et al., 2005; van Woerden et al.,
2007; Mulherkar and Jana, 2010; Ehlen et al., 2015). AS mice
also exhibit deficits in multiple forms of synaptic plasticity
such as long-term potentiation (LTP), long-term depression
(LTD), metabotropic glutamate receptor (mGluR)-dependent
LTD, homeostatic scaling, and ocular dominance plasticity
(Figure 5; Jiang et al., 1998; Weeber et al., 2003; Dindot et al.,
2008; Yashiro et al., 2009; Sato and Stryker, 2010; Pastuzyn and
Shepherd, 2017).
The anatomical changes in AS have also been studied in great
detail. In vertebrates, changes in dendritic spine dynamics are
associated with alterations in learning, plasticity, and behavior
throughout development (Dindot et al., 2008; Silva-Santos et al.,
2015; Valluy et al., 2015; Pastuzyn and Shepherd, 2017). Notably,
the density of dendritic spines was found to be reduced in
a postmortem human AS patient using a traditional method
of Golgi staining (Jay et al., 1991). Similarly, Ube3am−/p+ (AS)
mice have a decrease in dendritic spines, an absence of normal
induction of LTD and LTP in the visual cortex, and have
defective ocular dominance plasticity (Dindot et al., 2008; Yashiro
et al., 2009; Sato and Stryker, 2010). The use of two-photon
microscopy has allowed researchers to increase the depth of
imaging in living tissue and provide longitudinal changes in
functional connectivity, cortical response, and neural activity
with limited phototoxicity (Yang and Yuste, 2017). To observe
changes in dendritic spine dynamics, AS mice were crossed
with Thy1-GFP males (Feng et al., 2000; Kim et al., 2016). The
resulting offspring of this cross allowed GFP expression in Layer
5 pyramidal neurons in both wild type (WT) and AS mice (Kim
et al., 2016). Although dendritic spine density was not altered in
AS mice, dendritic spine elimination was significantly increased
during the end of the first month of postnatal life. However,
enhanced spine elimination could be rescued when AS mice
were deprived of visual experience by dark rearing (Kim et al.,
2016).
FIGURE 3 | Rare neurological disorders (RNDs) and E3 ligase gene
associations. Diagram of RNDs correlated with E3 ligase genes that are
mutated in specific disorders. Diseases shaded in blue indicate multiple genes
linked to that disorder. Genes highlighted in dark gray are shared between
several diseases. Figures were generated using Graphviz (www.graphviz.org).
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FIGURE 4 | Rare neurological disorders (RNDs) and their associated E3 ligase domain type. RNDs that contain mutations in E3 ligase domains (blue). RING
domain-containing E3 ligases account for ∼53% of known mutated E3 ligase genes in RNDs. Figures were generated using Graphviz (www.graphviz.org).
the deficits in postnatal brain growth and pathophysiology can be
understood by examining the mechanism of this phenotype and
the developmental consequences due to loss of UBE3A.
Optogenetics is another tool used to measure how neural
populations affect the circuitry and function of the brain leading
to behavioral phenotypes. This technique typically uses light
to manipulate the activity of light-sensitive ion channels to
spatially and temporally control cells in select brain regions
(Klapoetke et al., 2014; Deisseroth, 2015; Yang and Yuste, 2017).
Previously, a loss of UBE3A was found to enhance dopamine
release in the mesoaccumbal pathway (Riday et al., 2012;
Berrios et al., 2016). To evaluate the role of dopamine release
in consummatory behavior, optogenetics was used to evaluate
motivational behavior in a conditional AS model (Ube3aFLOX/p+ )
by crossing these mice to those that express CRE recombinase
Gross anatomical differences have been observed in multiple
brain regions in the AS mouse model (Judson et al., 2017).
AS mice exhibit microcephaly and have significant reductions
in white matter tracts. These microstructural abnormalities
were investigated using diffusion tensor imaging (DTI), a tool
that provides unique information of the preferred orientation,
myelination, and density in white matter specifically in axon
bundles in vivo (Basser and Pierpaoli, 1996; Goodlett et al.,
2009). Using electron microscopy, a decrease in axon caliber
(reduced cross-sectional diameter) in myelinated axons was
identified within the corpus callosum and sciatic nerves, which
later revealed slower action potential rise kinetics compared to
controls (Judson et al., 2017). Generally, microcephaly is linked to
early neurological phenotypes such as hypotonia and seizures in
infants (Fryburg et al., 1991). Therefore, the relationship between
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performance using a battery of behavioral tests (rotarod, marble
burying, open field, nest building, forced swim test, and epilepsy)
similar to the traditional AS mouse model (Silva-Santos et al.,
2015). CRE-dependent reinstatement of UBE3A rescued motor
deficits in adolescent mice. However, other AS behaviors such as
anxiety, repetitive behavior, and epilepsy could only be rescued
during early development (Silva-Santos et al., 2015).
Electrophysiology, specifically local field potential recordings,
allow researchers to understand dynamic neural networks by
measuring action potentials and graded potentials that reflect
synaptic activity in the neural network (Herreras, 2016). Using
this method, full recovery of hippocampal LTP was found at every
time point of UBE3A reinstatement (Silva-Santos et al., 2015).
Using in vivo patch-clamp electrophysiology in the same
mouse model above, AS mice were found to have increased
excitability and reduced orientation tuning in regularspiking GABA-ergic pyramidal neurons. However crossing
Ube3aSTOP/p+ with Gad2-CRE mice to specifically reinstate
UBE3A in interneurons could rescue orientation tuning
(Wallace et al., 2017).
A UBE3A reporter mouse was initially developed to assess
regions in which UBE3A was imprinted (Dindot et al.,
2008). The UBE3A-Yellow fluorescent protein knock-in mouse
(Ube3am+/pYFP ) was used to identify compounds to unsilence the
paternal Ube3a allele. The rationale behind this work was that the
majority of AS individuals have a maternally inherited disruption
of UBE3A unlike the paternal copy which is normal, but is not
expressed due to epigenetic modifications (Lalande and Calciano,
2007). Using the Ube3am+/pYFP knock-in mouse in a highcontent drug screen, topoisomerase inhibitors were found to
unsilence the paternal Ube3a allele (Huang et al., 2012). Notably,
the topoisomerase I inhibitor, topotecan, upregulated neuronal
UBE3A expression in an AS mouse and downregulated Ube3aATS and Snrpn (Small Nuclear Ribonucleoprotein Polypeptide N)
paternal gene expression in the brain in vivo (Huang et al., 2012).
Another corresponding study also used Ube3am+/pYFP knock-in
mice to test the efficiency of antisense oligonucleotides (ASOs)
in depleting the Ube3a-ATS as another strategy to unsilence the
paternal allele of UBE3A (Meng et al., 2015). The targeting of the
paternal dormant allele provides a potential treatment option for
AS by focusing on epigenetic modifications.
The development of AS patient-derived iPSCs has allowed
researchers to study AS in a more human relevant context.
(Chamberlain et al., 2010; Russo et al., 2015). These lines
have been useful in studying the exact genomic disruption
afflicted in AS patients and to understand human epigenetic
UBE3A regulation to assist in identifying novel therapeutic
strategies (Stanurova et al., 2016; Takahashi et al., 2017). ASderived iPSCs have an increase in resting membrane potentials,
decreased spontaneous synaptic currents, and a loss of LTP
induction (Fink et al., 2017). These phenotypes could be rescued
by treating AS-derived iPSCs with topotecan to unsilence the
UBE3A paternal allele. Treatment with topotecan resulted in an
increase in UBE3A mRNA expression which led to a shift to a
more hyperpolarized resting membrane potential and restoration
of action potential firing to control levels promoting normal
neuronal excitability (Fink et al., 2017). Importantly, targeting the
FIGURE 5 | Characteristic features of gene mutations in Ube3a observed in
Angelman syndrome. Angelman syndrome mouse models show abnormal
sleep patterns that are accompanied by EEG recordings displaying increased
delta power and dynamic delta oscillations; mouse strain-dependent seizures;
learning impairments including intellectual disability and developmental delay.
Specific symptoms vary in individual cases. In AS mouse models, maternal
deletion of Ube3a causes microcephaly and leads to multiple deficits in
synaptic plasticity such as decreased LTP induction, deficits in
mGluR-dependent LTD and homeostatic scaling. Mutations in UBE3A alter
neuronal morphology that includes decreased axon caliber and spine density,
and increased spine elimination in select brain regions.
specifically in tyrosine hydroxylase neurons (THCRE ). These
mice were then transduced with a CRE-dependent adenoassociated virus (AAV5)-channelrhodopsin-2 (H134R) fused to
an enhanced yellow fluorescent protein (ChR2-eYFP) into the
ventral tegmental area and an optical fiber was placed above
the nucleus accumbens (Berrios et al., 2016). Mice were then
trained on a specific schedule to nose-poke during optical
stimulation. Mice with a loss of UBE3A in tyrosine-hydroxylase
neurons demonstrated increased reward-seeking behavior via
optical self-stimulation by suppressing the co-release of gammaaminobutyric acid (GABA), an inhibitory neurotransmitter, in a
non-canonical pathway (Berrios et al., 2016).
The generation of the UBE3A reinstatement model has
allowed researchers to define neurodevelopmental windows that
may rescue AS-related phenotypes. A conditional reinstatement
mouse model of Ube3a was created using a CRE-dependent
reinstatement of maternal Ube3a (Ube3aSTOP/p+ ). Mice lacking
maternal Ube3a displayed consistent impaired behavioral
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Epilepsy is a neurological disorder involving a long-term
susceptibility to seizures caused by atypical neuronal activity in
the brain (Fisher et al., 2005). About 3.4 million people, both
adults and children, in the U.S. have active epilepsy (Zach and
Kobau, 2017). Although there are many classifications of epileptic
disorders, for the purpose of this review, we will only focus on
specific rare epileptic types associated with E3 ligases.
Infantile spasms (IS) are characterized by the onset of seizures
that occur in clusters during the first year of life. IS patients
display irregular EEG readings known as hypsarrhythmia that is
thought to cause developmental dysfunction (Lux and Osborne,
2004). The incidence of IS occurs in about 0.025–0.05% of live
births (Taghdiri and Nemati, 2014). IS is caused by a deletion in
the chromosome region 1p36. This region was identified using
fluorescence in situ hybridization (FISH), a cytogenetic technique
that uses fluorescence microscopy to visualize fluorescent probes
designed to detect complementary nucleic acid sequences on
chromosomes (Ratan et al., 2017). The fluorescent probe is RNA
or single-stranded DNA labeled with fluorophores through nick
translation or PCR that hybridize to its target with antibodies
or biotin (Levsky and Singer, 2003). In human case studies, one
subject was identified to have a chromosome deletion with copy
number variation in the KLHL17 (Kelch-like family member 17)
gene (Figure 3 and Supplementary Table 2). This gene encodes
an E3 ligase that is thought to play a role in actin-based neuronal
function (Paciorkowski et al., 2011). In this study, the use of
FISH was helpful in screening E3 ligases selectively to epileptic
disorders. Even so, more studies would need to prove that there is
a more critical region for IS that includes KLHL17 and to confirm
that KLHL17 is a causative gene for IS.
Adult myoclonic epilepsy (AME) is associated with myoclonic
jerks and twitches as well as finger shaking movement.
Worldwide prevalence of AMEs remains unknown, but there
are geographic variations of different genes associated with
this disorder (Delgado-Escueta et al., 2003). AME is linked to
missense mutations in the HECT E3 ligase, UBR5 (Figure 3 and
Supplementary Table 2; Kato et al., 2012). UBR5 was identified
using whole exome enrichment and sequencing (WES) via
NGS by using RNA probes to find single nucleotide variants
(SNVs) and single nucleotide polymorphisms (SNPs) (Chen
et al., 2015). While NGS is a type of technology that allows
for high throughput sequencing, WES is a type of NGS that is
more focused on sequencing protein-coding regions of a genome
that contain mutations (Seleman et al., 2017). UBR5 mutations
were identified in affected family members with AME but not
in unaffected groups or unaffected family members (Kato et al.,
2012). UBR5 has many functional roles including maturation and
transcriptional regulation of mRNA, cell cycle, extraembryonic
development, tumor suppression and regulation of the DNA
topoisomerase II binding protein (TDP2). Other functions
include suppression of another E3 ligase, RNF168, in response
to DNA damage and prevention of growth of ubiquitinated
chromatin in response to chromosomal damage (Gudjonsson
et al., 2012). Similar to IS, further studies are needed to verify the
importance of mutations in the UBR5 gene and its association
with AME. Researchers have only begun to scratch the surface
of finding altered E3 ligase functions in epilepsy making it
silenced paternal allele in AS patients might alleviate AS-related
phenotypes such as intellectual impairments and developmental
delays by increasing synaptic events (Fink et al., 2017). In another
study, targeting CGI methylation de novo via introducing a
CpG-free cassette into AS patient-derived iPSCs was able to
correct abnormal DNA methylation and result in normal UBE3A
expression in DA neurons (Takahashi et al., 2017).
In parallel to the use of transgenic mice and human
iPSCs, clinicians have sought to discover indicators specific to
AS patients. One of the methods used in human cases was
electroencephalography (EEG) for which AS patients tend to
display theta rhythmicity, epileptiform spike-wave changes, and
increased delta rhythmicity (Vendrame et al., 2012). Delta power
in the AS mouse and in AS children was compared. Results
from these studies demonstrated an increase in delta power
during wakefulness and sleep in both AS mice and children with
AS compared to matched controls (Sidorov et al., 2017). These
studies reveal, that in AS, loss of UBE3A results in large-scale
disruptions in rhythmic neural activity and shows that EEGs may
serve as a potential biomarker for not just AS, but for other RNDs
that have seizure phenotypes.
It is worth noting duplication of the 15q11-q13 region
of the maternal chromosome harboring the UBE3A gene
is also a common and highly penetrant factor of autism
spectrum disorder (ASD) pathogenesis (Figure 1 and
Supplementary Table 1), and an increased dosage of the
UBE3A gene is associated with developmental delay and
neuropsychiatric phenotypes (Cook et al., 1997; Glessner et al.,
2009; Noor et al., 2015). UBE3A can function as both an E3 ligase
and a transcriptional co-activator (Scheffner et al., 1993; Dindot
et al., 2008). It is expressed monoallelically in neurons and is
involved in many previously stated functions such as maintaining
the proper level of dendritic branching, synapse formation, and
controlling the frequency of mEPSCs (Lu et al., 2009; Greer et al.,
2010; Margolis et al., 2010; Khatri et al., 2017). Because previous
research has parsed out the importance of expression sensitivity
of UBE3A in two disorders, developing drugs that can control the
expression of either the paternal or maternal allele or those that
modulate neuronal activity would be beneficial to this patient
population. Moreover, due to the emergence of early symptoms
in AS and ASD, individuals with UBE3A disruptions can be
monitored throughout their lifetime to prevent or alleviate
ongoing symptoms such as seizures or ataxia.
Other Rare Neurological Disorders
Mutation in E3 ligase genes are associated with a vast multitude of
RNDs (Figure 3 and Supplementary Table 2). For the majority
of RNDs, there is not strong supporting evidence to indicate a
causal link between them. Many of the RNDs mentioned in detail
below have implied a possible relationship between the RND and
an E3 ligase through familial case studies by looking at probable
critical regions on chromosomes to screen out less important
genes (Sekine and Makino, 2017).
Epilepsy
Disorders that encompass seizure-like phenotypes have links
to neurodegeneration (Wong, 2013; Dingledine et al., 2014).
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Considering hypogonadotropic hypogonadism is another
feature of GHS, the endocrine system in GHS individuals was
examined. Decreased levels of luteinizing hormone (LH) and
pituitary dysfunction were detected indicating gonadotropinreleasing hormone (GnRH) secretion deficiencies; indeed, when
robust pulses of GnRH were administered, gonadotropin levels
and reproductive function were restored (Margolin et al.,
2013). Another clinical case study showed cerebellar and
cortical atrophy through the use of fMRIs and fluid-attenuated
inversion recovery (FLAIR) brain imaging in two patients with
homozygous mutations of a splice variant of RNF216 (Alqwaifly
and Bohlega, 2016). FLAIR is a MRI technique that contrasts
the tissue T2 prolongation and the cerebrospinal fluid signal so
that lesions near the cerebrospinal fluid are revealed (Saranathan
et al., 2017). These patients also confirmed low levels of LH and
additionally testosterone, but testosterone treatment normalized
secondary sexual characteristics (Alqwaifly and Bohlega, 2016).
A recent case study identified additional mutations in RNF216
in a patient with GHS who had progressive cognitive decline
that correlated with high signal intensity within the white matter
of both cerebral hemispheres with gray matter lesions in the
thalami, cerebellar atrophy, and high T2 signals in the midbrain
(Mehmood et al., 2017). These clinical case studies support the
strong relationship between behavioral phenotypes and their
corresponding biological insults.
As opposed to using mouse models to support the role of
RNF216 in GHS, zebrafish were used to test the functionality
of the gene by injecting morpholino oligonucleotides (MO) in
order to silence rnf216. This resulted in decreased size of the eye
cup, optic tecta, and head size along with disorganization of the
cerebellum. These phenotypes were rescued with co-injection of
human RNF216 mRNA (Margolin et al., 2013). Complementing
these data with transgenic mouse lines would provide a strong
foundation to support the genetic studies of familial variability
both in vitro and in vivo.
RNF216 encodes multiple RING finger E3 ligase isoforms
(TRIAD3A-TRIAD3E) and plays a major role in inflammation
(Chen et al., 2002; Chuang and Ulevitch, 2004; Fearns et al., 2006;
Nakhaei et al., 2009; Shahjahan Miah et al., 2011; Xu et al., 2014).
The first neuronal function for RNF216 was the identification
of the immediate early gene, activity-regulated cytoskeletalassociated protein (Arc), as a substrate of TRIAD3A. TRIAD3A
was found to directly ubiquitinate Arc and mediate its turnover
by the UPS in mouse primary neurons (Mabb et al., 2014).
Using a technique called total internal reflection fluorescence
microscopy (TIRFM), TRIAD3A was also found to localize at
clathrin-coated pits resulting in altered trafficking of α-amino-3hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors,
principal excitatory receptors that mediate the majority of fast
excitatory synaptic transmission in the nervous system (Mabb
et al., 2014). Using shRNA to reduce levels of TRIAD3A, Arcdependent forms of synaptic plasticity were found to be altered
most likely due to disruptions in AMPA receptor trafficking
(Mabb et al., 2014). Additionally, viral transduction of Triad3
shRNA in the hippocampus of mice led to deficits in learning in
the Morris water maze, a spatial-dependent learning task (Husain
et al., 2017).
difficult to currently manage epileptic patients with these specific
gene mutations due to limited research in understanding the
role of ubiquitinated proteins in epilepsy. Along with further
investigation of E3 ligases, animal models with knock-out
genes such as KLHL17 or UBR5 or even knock-in mouse
models would be beneficial in determining the functionality
of these genes for both in vitro and in vivo experiments.
The isolation of iPSC cells from individuals with epilepsy and
brain imaging tools such as EEGs might be useful to identify
biomarkers.
Gordon Holmes Syndrome
Gordon Holmes syndrome (GHS) is another RND that
has recently gained more attention. The clinical symptoms
include ataxia and hypogonadotropic hypogonadism, cognitive
impairment, dysarthria, cerebellar ataxia, and in some cases
dementia (Haines et al., 2007; Margolin et al., 2013; Alqwaifly
and Bohlega, 2016). GHS is part of a subset of disorders called
autosomal recessive hereditary cerebellar ataxias (ARCA) with
extracerebellar symptoms such as dementia (Heimdal et al.,
2014). The prevalence of GHS remains unknown. Whole exome
sequencing studies have established that homozygous mutations
in the E3 ligase STIP1 homology and U-Box containing protein 1
(STUB1) also known as carboxy terminus of Hsp70-interacting
protein (CHIP), results in ataxia and hypogonadism with a
frequency of 2.3% in GHS patients (Shi et al., 2014; Hayer
et al., 2017; Figure 3 and Supplementary Table 2). Evidence in
clinical familial cases have also demonstrated that mutations
in STUB1/CHIP were identified in patients with ARCA along
with cognitive impairment (Heimdal et al., 2014). Functionally,
STUB1/CHIP is a gene that encodes the protein CHIP which is
a U-box dependent E3 ligase involved in chaperoning proteins
(Jiang et al., 2001). In assessing neurological behaviors, Chip
knockout mice have decreased motor, sensory and cognitive
function. These impairments were also associated with abnormal
cellular morphology of Purkinje cells and other cortical cell layers
resulting in cerebellar dysfunction (Shi et al., 2014).
Markedly, GHS has been associated with both missense and
nonsense mutations in the RBR E3 ligase, RNF216/TRIAD3
(Margolin et al., 2013) (Figure 3 and Supplementary Table 2).
In familial genetic studies, patients diagnosed with ataxia and
hypogonadotropic hypogonadism had compound heterozygous
mutations in RNF216 whose variants were predicted to be
deleterious compared to controls (Margolin et al., 2013). This
implicated RNF216 as a causative gene for this disorder
(Margolin et al., 2013). In one deceased patient, histopathological
examination revealed atrophy of the cerebellum, gliosis, loss of
inferior olivary neurons and cerebellar Purkinje cells, and loss
of neurons in hippocampal regions CA3 and CA4. Moreover,
ubiquitin-immunoreactive nuclear inclusions were found in the
CA1, CA2, and dentate gyrus of the hippocampus further
providing an anatomical basis for dementia. Longitudinal
studies of the clinical symptoms of GHS patients identified
dysarthria in early stages of life, while ataxia and dementia
developed later on in adulthood indicated by neuroimaging
results that revealed cerebellar and cortical atrophy (Margolin
et al., 2013).
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of the brain (Ma et al., 2016). This disease has recently gained
attention because it is thought to be a causative factor of stroke
in both adults and children (Veeravagu et al., 2008). Although
the progression of pathogenesis and prevalence is still unclear,
missense mutations in RNF213 have been identified in 95%
of familial cases and 73% of sporadic clinical cases (Kamada
et al., 2011) (Figure 3 and Supplementary Table 2). Among the
30 RNF213 variants listed from the Human Gene Mutation
Database (HGMD), R4810K is the only variant that is strongly
associated with MMD (Jang et al., 2017; Supplementary Table 2).
A familial clinical case showed one patient with the R4810K
mutation did not show any abnormalities with neuroimaging
tools during childhood, but was diagnosed with MMD 10 years
later after showing symptoms (Aoyama et al., 2017). This suggests
that determining the time course of disease progression is an
important factor in diagnosis and treatment.
The role of RNF213 in MMD was examined by subjecting
WT mice to transient middle cerebral artery occlusion (tMCAO)
and measuring mRNA expression of RNF213 both by in situ
hybridization and RT-PCR, finding that RNF213 was upregulated
compared to controls and its expression was predominantly in
neurons (Sato-Maeda et al., 2016). A MMD mouse model was
created to produce homozygous recessive RNF213 (RNF213−/− )
animals whose cervical and cranial arteries were examined using
magnetic resonance angiography (MRA) (Sonobe et al., 2014).
Although there was no difference in MRA readings between
WT and transgenic mice, common carotid artery ligation which
induced vascular hyperplasia, resulted in thinner intima and
medial layers in RNF213−/− mice compared to WT controls that
exhibited hyperplasia (Sonobe et al., 2014). This supports a role
of RNF213 in brain ischemia, a symptom of MMD, but further
studies are needed to understand the mechanism of RNF213
action in MMD. Notably, iPSCs and iPSC-derived vascular
endothelial cells (iPESCs) were taken from MMD patients that
had reduced angiogenic activity. Microarrays confirmed that
many mitotic-phase associated genes and securin, an inducer
of angiogenesis and inhibitor of premature sister chromatin
separation, were downregulated with this RNF213 genotype
(Hitomi et al., 2013). RNAi-mediated depletion of securin also
impaired tube formation without affecting proliferation of iPSCs
(Hitomi et al., 2013). Using iPSCs can be useful as an in vitro
model to study not only the pathophysiology of RNF213, but also
to investigate specific drug targets for therapeutic intervention.
Due to STUB1/CHIP’s role in directing chaperone proteins
for proteasomal degradation, patients with this mutation could
partake in treatment options that target these substrates to
promote the growth and maintenance of Purkinje cells and other
cortical cell layers. Regarding RNF216, particularly TRIAD3A,
therapeutic inventions to induce Arc-dependent forms of
synaptic plasticity could possibly prevent or at least delay the
dementia phenotype. In conjunction, targeting substrates of
the inflammatory pathway could prevent abnormal cell death.
Research to elucidate the roles of RNF216 isoforms would be
helpful in creating viable treatment options for patients. The
generation of additional transgenic animal models and the use
of iPSCs would be beneficial in determining the effects of both
STUB1 and RNF216 disruptions on a cellular level and would
aid in establishing additional substrates and pathways leading to
behavioral phenotypes.
Louis Bar Syndrome
Louis Bar syndrome, commonly referred to as ataxiatelangiectasia (AT), is identified by its symptoms of ataxia,
telangiectasia, elevated alpha-fetoprotein, microcephaly,
pulmonary
failure,
radiosensitivity,
immunodeficiency,
dysmorphic features, and learning difficulties with a prevalence
of 0.001–0.0025% in live births (Boder and Sedgwick, 1970;
Swift et al., 1986; Richard and Susan, 1999). Clinical studies
showed an occurrence of homozygous nonsense mutations
in RNF168 in patients with AT and radiosensitivity (Figure 3
and Supplementary Table 2). In addition, when screening
for irradiation-induced nuclear foci containing 53BP1, AT
lymphoblastoid cells showed a deficiency in the RNF168
pathway (Devgan et al., 2011). In vitro studies using shRNA
showed that knock-down of RNF168, RNF8 and 53BP1 in a
CH12F3-2 mouse B cell line resulted in a significant reduction
in class-switch recombination (CSR) (Ramachandran et al.,
2010). RNF168 plays a pivotal role following DNA double strand
breaks (DSBs). During DNA damage, RNF168 is recruited to
H2A-type histones and amplifies H2A lysine 63-linked ubiquitin
conjugates mediated by another E3 ligase RNF8 (Stewart et al.,
2009). This results in the accumulation of 53BP1, a protein
important for double-stranded break repair, and BRCA1, a
tumor suppressor protein, that are recruited to the sites of DNA
damage critical for mediating cell cycle checkpoints and DNA
repair (Stewart et al., 2009). While studying the immunology and
radiological aspects of Louis-Bar syndrome is valuable, a nice
correlate would be to determine if mutations in RNF168 causes
other symptoms such as ataxia, telangiectasia or pulmonary
failure. This would involve the use of transgenic animal models
to study behavioral phenotypes. It would also be conducive to
give attention to knock-out or overexpression of RNF168 in
other cell types such as neurons or glial cells to determine if
mutations in these cell types may result in impaired behavioral
phenotypes.
Juberg-Marsidi Syndrome
Juberg-Marsidi syndrome is a rare congenital X-linked
disorder that specifically affects males. Symptoms consist
of mental retardation, delay in developmental milestones,
muscle weakness, hypotonia, growth retardation, deafness,
microgenitalism, microcephaly, and additional physical
abnormalities (Villard et al., 1996). The prevalence remains
unknown. Using NGS, Juberg-Marsidi syndrome was found to
be associated with mutations in the HECT E3 ubiquitin ligase,
HUWE1, implicating it as a possible candidate gene for this
X-linked disorder (Nava et al., 2012; Friez et al., 2016; Figure 3
and Supplementary Table 2). In evaluating the function of
HUWE1 and its substrates, a conditional knock-out mouse
Moyamoya Disease
Moyamoya Disease (MMD) is an RND that shows unique
symptoms of steno-occlusion of the terminal side of the internal
carotid artery causing abnormal vascular networks at the base
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E3 Ligase Mutations in Neurological Disorders
cost prohibitive (Goldfeder et al., 2017). The studies discussed
above show the benefits of using rapid and cost-effective NGS
platforms in identifying gene variants and novel disease genes.
Narrowing down the genetic causes of neurological diseases
will allow clinicians and health care professionals to advise and
administer specialized treatments at appropriate times to assist
in the reduction of disease burden over time.
The prevalence of E3 ligase disruptions in such a
broad array of neurological diseases suggests disruption
in ubiquitin pathways may be a major driving force. The
abundance of E3 ligase genes mutated in neurological disease
(Supplementary Tables 1, 2) indicates that targeting the
ubiquitin pathway might have utility for a range of neurological
disorders. However, this serves as a great challenge to researchers
given our lack of a comprehensive understanding of E3 ligases
and their role in neurodevelopment, neuronal maintenance,
and a lack of information of E3 ligase substrates. This is further
clouded in difficulties in developing intervention therapies due
to the diversity and complexity of the ubiquitin pathway (Huang
and Dixit, 2016). It is worth noting that for the few drugs that
have been developed to target the ubiquitin pathway, most are
meant to inhibit or disrupt function. Considering many of the
E3 ligases mutated in neurological disease are related to a loss of
enzyme function, inhibitors targeting these enzymes would not
be beneficial (Bondeson et al., 2015; Galdeano, 2017). However,
the finding that there are multiple E3 ligases that are disrupted
in similar disease subsets (e.g., ASD) indicates a potential
nexus of biological and functional convergence (Figures 1, 3).
Intriguingly, with the exception of GHS, we found that RNDs
appear to be associated with one type of E3 ligase domain class
(Figure 4), whereas CNDs tend to share E3 ligase domain classes
(Figure 2).
The emergence of methods such as hydrophobic tagging
might be useful for the targeting of E3 ligase substrates that
undergo protein degradation (Neklesa et al., 2011; Huang and
Dixit, 2016) but this requires the identification of substrates.
Moreover, E3 ligase substrates may undergo ubiquitination that
does not lead to subsequent degradation by the UPS. In order
to maximize the potential for therapeutic treatments especially
for RNDs, future studies that answer the following questions
are warranted: What is the full list of mutated genes that
encode for E3 ligases in neurological disease? NGS and access
to patient populations for RNDs and CNDs would assist in
this endeavor. What is the full range of substrates that are
targeted by disease-associated E3 ligases? One of the most
extensive lists exists for the E3 ligase Parkin but other E3
ligase substrates remain elusive (Panicker et al., 2017). What
are the functions of the E3 ligases that are disrupted in
neurological disorders? Note that for many RNDs, E3 ligase
function in the nervous system is undefined. Are E3 ligases
that are mutated in similar disorders have overlapping biological
functions? Very little is known about how these enzymes function
in the nervous system. Finally, for the ever-growing list of
CNDs and RNDs that exhibit symptomatic heterogeneity, how
does one select drug targets and develop viable therapeutic
treatments? This, of course, will be the greatest of challenges for
researchers.
model was generated to delete the HECT domain of HUWE1.
Mice were crossed with GFAP-CRE deleter mice to specifically
target HUWE1 deletion in cerebellar granule neuron precursors
(CGNPs) and radial glia (D’Arca et al., 2010). These mice
were found to have high lethality around postnatal day 21
and cerebellar abnormalities including defects in cell cycle
exit and granule cell differentiation with an ataxic phenotype
caused by uncontrolled proliferation of CNGPs. This was
associated with an increase in the abundance of a HUWE1
substrate, N-Myc (D’Arca et al., 2010). There are many different
functions of HUWE1 including regulating neural differentiation
and proliferation via catalyzing the polyubiquination and
degradation of MYCN, which encodes the N-myc oncoprotein;
ubiquitination of the tumor suppressor protein, p53; and
regulation of CDC6 levels, essential for DNA replication, after
DNA damage (Yoon et al., 2004; Hall et al., 2007; Zhao et al.,
2008). In parallel with the work mentioned above, it would
be favorable to determine how the overexpression of HUWE1
alters differentiation of the cerebellum. Indeed, disruption of
HUWE1 in human iPSCs would assist in establishing critical
developmental time points related to postnatal lethality.
Opitz G/BBB Syndrome
The Opitz G/BBB syndrome (OS) is another congenital disorder
that involves two forms: X-linked and autosomal dominant
found on chromosome 22. Both forms have similar abnormalities
due to defects of the midline structures which include growth
delay, microcephaly, polydactyly, cleft palate, mental retardation,
seizures, heart defects, hypertelorism, and deafness. (Robin
et al., 1996). The prevalence of this disease is unknown. In
particular, the X-linked form is caused by a mutation in
the MID1 gene, an E3 ligase that is a member of the Bbox family of zinc finger proteins with a RING-finger motif
involved in anchoring proteins to microtubules (Quaderi et al.,
1997; Figure 3 and Supplementary Table 2). In vivo studies
using a Mid1-null mouse line demonstrated OS phenotypes
observed in affected humans. For example, prenatal cerebellar
defects lead to dysfunction of primitive fissures and definitive
boundaries resulting in motor discoordination and motor
learning deficiencies (Lancioni et al., 2010). This work provides
insight into the genetic causes underlying the behavior observed
in OS. The use of primary neuron cultures and stem cells to
understand how differentiation of the midline is affected and
elucidation of the pathway the underlies this mechanism would
be informative in understanding the origin leading to these OS
symptomologies.
CONCLUSIONS
The current studies on E3 ligases and their implication in
neurological disorders is still an open field where research
using diverse, emerging technologies would benefit. Molecular
diagnosis of neurological disorders requires accurate, efficient,
and cost-effective methods. Traditionally, standard PCR was
helpful in detecting short sequences of repeat expansions. The
emergence of Sanger sequencing allowed for sequencing of the
entire human genome but was considerably time-consuming and
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AUTHOR CONTRIBUTIONS
was supported by The Whitehall Foundation (Grant 201705-35) and Georgia State University laboratory startup funds
to AM.
YH and AC: generated the list of E3 ligases implicated in
neurological disorders found in Supplementary Tables 1, 2. AG
and AM: Validated the list of E3 ligases and wrote the manuscript;
AG and YZ: Created the figures.
SUPPLEMENTARY MATERIAL
The Supplementary Material for this article can be found
online at: https://www.frontiersin.org/articles/10.3389/fgene.
2018.00029/full#supplementary-material
ACKNOWLEDGMENTS
We would like to thank the Rare Genomics Institute for
the opportunity to submit this review on E3 ligases in Rare
Neurological Disorders, Mohammad Ghane, Jason Yi and
Jun Yin for critical review of the manuscript. This work
Supplementary Table 1 | List of E3 ubiquitin ligases mutated in common
neurological disorders (CNDs).
Supplementary Table 2 | List of E3 ubiquitin ligases mutated in rare neurological
disorders (RNDs).
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GLOSSARY
ataxia: inability to coordinate voluntary muscle movements due to dysfunction of the central nervous system, not due to muscle
weakness
bradykinesia: extreme slowness in movements and reflexes
dysarthria: slurred speech due to dysfunction of the central nervous system
dystonia: abnormality of movement and muscle tone
gliosis: abnormal production of glia cells
homeostatic scaling: form of synaptic plasticity in which single neurons can regulate their own excitability in relation to network
activity
hyperplasia: abnormal production of cells in tissues
hyperreflexia: overactivity of physiological reflexes
hypertelorism: abnormal increase in distance between two body parts (e.g. between the eyes)
hypotonia: having deficient muscle tone
hypogonadotropic hypogonadism: decreased activity of the gonads (testes and ovaries) due to deficiency of gonadotropins (LH and
FSH) and diminished levels of sex steroid hormones
hypsarrhythmia: abnormal encephalogram characterized by disorganized arrangement of spikes
long term depression (LTD): a form of activity-dependent plasticity that weakens a specific set of synapses due to a patterned stimulus
that reduces the excitatory postsynaptic potential
long term potentiation (LTP): a form of activity-dependent plasticity that persistently strengthens a set of synapses due to a patterned
stimulus
microcephaly: abnormal smallness in circumference of the head that occurs at birth or within the first few years of life
myoclonic jerk: brief, involuntary twitching due to rapid contraction and relaxation of muscles
nuclear inclusion: clusters of a substance (e.g. proteins) that occur in the nucleus of a cell
ocular dominance plasticity: stripes of neurons located in the visual cortex that span many cortical layers that preferentially respond
from one eye or another and are modified by activity-dependent changes in neuronal connections during a critical period
telangiectasia: abnormal dilation of the subcutaneous vascular system
radiosensitivity: quality of being quick to respond to slight changes in radiant energy
steno-occulsion: proximal narrowing or blockage of a blood vessel
telangiectasia: threadlike red patterns on the skin caused by widened venules
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