Possible
Roles of the Transglutaminase-Catalyzed Reactions in the Pathogenesis of Human Neurodegenerative
Diseases
Martina
Iannaccone, Enrica Serretiello, Nicola G. Gatta, Vittorio Gentile
Martina
Iannaccone, Enrica Serretiello, Nicola G. Gatta, Vittorio Gentile, Department of Biochemistry, Biophysics and General Pathology, Second University of Naples,
via Costantinopoli 16, 80138 Naples, Italy
Correspondence to: Vittorio Gentile, Department of
Biochemistry, Biophysics and
General Pathology, Second University of Naples, via Costantinopoli 16, 80138
Naples, Italy.
Email: vittorio.gentile@unina2.it
Telephone: +39-81-5665870
Fax:
+39-81-5665863
Received: May 20, 2015
Revised: July 28, 2015
Accepted: August 1, 2015
Published online: September 22, 2015
ABSTRACT
Transglutaminases
are Ca2+-dependent enzymes which catalyze post-translational
modifications of proteins. The main activity of these enzymes is the
cross-linking of glutaminyl residues of a protein/peptide substrate to lysyl
residues of a protein/peptide co-substrate. In addition to lysyl residues,
other second nucleophilic co-substrates may include monoamines or polyamines
(to form mono- or bi-substituted /crosslinked adducts) or ¨COH groups (to form
ester linkages). In absence of co-substrates, the nucleophile may be water,
resulting in the net deamidation of the glutaminyl residue. Transglutaminase
activity has been suggested to be involved in molecular mechanisms responsible
for both physiological or pathological processes. In particular,
transglutaminase activity has been shown to be responsible for a widespread
human autoimmune disease, the Celiac Disease. Interestingly, neurodegenerative
diseases, such as Alzheimer¡¯s Disease, Parkinson¡¯s Disease, supranuclear palsy,
Huntington¡¯s Disease and other diseases, are characterized in part by aberrant
cerebral transglutaminase activity and by increased cross-linked proteins in
affected brains. This review focuses on the possible molecular mechanisms
responsible for such diseases and on the possible use of transglutaminase
inhibitors for patients with diseases characterized by aberrant
transglutaminase activity.
© 2015 ACT. All
rights reserved.
Key words: Transglutaminases; Post-translational modifications of
proteins; Protein aggregation; Neurodegenerative diseases; Transglutaminase
inhibitors.
Iannaccone M,
Serretiello E, Gatta NG, Gentile V. Possible Roles of the
Transglutaminase-Catalyzed Reactions in the Pathogenesis of Human
Neurodegenerative Diseases. Journal of
Biochemistry and Molecular Biology Research 2015; 1(3): 72-79 Available from: URL:
http://www.ghrnet.org/index.php/jbmbr/article/view/1219
THE BIOCHEMISTRY OF THE
TRANSGLUTAMINASES
Transglutaminases (TGs, E.C. 2.3.2.13) are Ca2+-dependent
enzymes which catalyze post-translational modifications of proteins. Examples
of TG-catalyzed reactions include: I) acyl transfer between the -carboxamide group
of a protein/polypeptide glutaminyl residue and the -amino group of a
protein/polypeptide lysyl residue; II) attachment of a polyamine to the -carboxamide of a
glutaminyl residue; III) deamidation of the -carboxamide group of a
protein/polypeptide glutaminyl residue (Figure 1)[1,2]. The
reactions catalyzed by TGs occur by a two-step mechanism (ping-pong type),
(Figure 2). The transamidating activity of TGs is activated by the binding of
Ca2+, which exposes an active-site cysteine residue. This cysteine
residue reacts with the -carboxamide group of an incoming glutaminyl residue of a
protein/peptide substrate to yield a thioacyl-enzyme intermediate and ammonia,
(Figure 2, Step 1). The thioacyl-enzyme intermediate then reacts with a
nucleophilic primary amine substrate, resulting in the covalent attachment of
the amine-containing donor to the substrate glutaminyl acceptor and
regeneration of the cysteinyl residue at the active site, (Figure 2, Step 2).
If the primary amine is donated by the e-amino group of a lysyl residue in
a protein/polypeptide, a Ne-(-L-glutamyl)-L-lysine (GGEL) isopeptide bond is formed, (Figure 1,
example I). On the other hand, if a polyamine or another primary amine (e.g.
histamine, serotonin and others) acts as the amine donor, a -glutamylpolyamine
(or -glutamylamine)
residue is formed, (Figure 1, example II). It is also possible for a polyamine
to act as an N,N-bis-(-L-glutamyl)polyamine bridge between two glutaminyl acceptor residues
either on the same protein/polypeptide or between two proteins/polypeptides[3].
If there is no primary amine present, water may act as the attacking
nucleophile, resulting in the deamidation of glutaminyl residues to glutamyl
residues, (Figure 1, example III). Regarding the physiological roles played by
the transglutaminase activity, recently transglutaminase-catalyzed
polyamination of tubulin has been shown to stabilize axonal microtubules,
suggesting an important role for these reactions also during some physiological
processes, such as neurite outgrowth and axon maturation[4]. The
reactions catalyzed by TGs occur with little change in free energy and hence
should theoretically be reversible. However, under physiological conditions the
cross linking reactions catalyzed by TGs are usually irreversible. This
irreversibility partly results from the metabolic removal of ammonia from the
system and from thermodynamic considerations resulting from altered protein
conformation. Some scientific reports suggest that TGs may be able to catalyze
the hydrolysis of Ne-(-L-glutamyl)-L-lysine cross-links (GGEL) isopeptide bonds in some
soluble cross-linked proteins. Furthermore, it is likely that TGs can catalyze
the exchange of polyamines onto proteins[2]. In TG2 other catalytic
activities, such as the ability to hydrolyze GTP (or ATP) into GDP (or ADP) and
inorganic phosphate (Figure 1, example IV), a protein disulfide isomerase
activity (Figure 1, example V), and a kinase activity which phosphorylates histones,
retinoblastoma (RB) and P53 (Figure 1, example VI), are present, while only
some of these activities have been identified also in other TGs[5-8].
Numerous
experimental evidences indicate that some TGs are multifunctional proteins with
distinct and regulated enzymatic activities. In fact, under physiological
conditions, the transamidation activity of TGs is latent[10], while
other activities, recently identified, could be present. For example, in some
physiological states, when the concentration of Ca2+ increases, the
crosslinking activity of TGs may contribute to important biological processes.
As previously described, one of the most intriguing properties of some TGs,
such as TG2, is the ability to bind and hydrolyze GTP and, furthermore to bind
to GTP and Ca2+. GTP and Ca2+ regulate its enzymatic
activities, including protein cross-linking, in a reciprocal manner: the
binding of Ca2+ inhibits GTP-binding and GTP-binding inhibits the
transglutaminase cross-linking activity of the TG2[5]. Interestingly,
TG2 shows no sequence homology with heterotrimeric or low-molecular-weight
G-proteins, but there is evidence that TG2 (TG2/Gh) is involved in signal
transduction, and, therefore, TG2/Gh should also be classified as a
large molecular weight G-protein. Other studies, along with ours, showed that
TG2/Ghcan mediate the
activation of phospholipase C (PLC) by the 1b-adrenergic
receptor[10] and can modulate adenylyl cyclase activity[11].
TG2/Gh can also mediate
the activation of the d1 isoform of PLC and of maxi-K channels[12]. Interestingly,
the signaling function of TG2/Gh is preserved even with the mutagenic inactivation of its crosslinking
activity by the mutation of the active site cysteine residue[13].
THE
MOLECULAR BIOLOGY OF THE TRANSGLUTAMINASES
To date at least eight different TGs, distributed in the human body,
have been identified (Table 1)[14-19]. Complex gene expression
mechanisms regulate the physiological roles that these enzymes play in both the
intracellular and extracellular compartments. In the Nervous System, for
example, several forms of TGs are simultaneously expressed[20-22].
Moreover, several alternative splice variants of TGs, mostly in the 3´-end
region, have been identified in these last years[23]. Interestingly,
some of them are differently expressed in human pathologies, such as
Alzheimer¡¯s Disease (AD)[24]. On the basis of their ubiquitous
expression and their biological roles, we may speculate that the absence of
these enzymes would be lethal. However, this does not always seem to be the
case, since, for example, null mutants of the TG2 are usually phenotypically
normal at birth[12,25,26]. This result may be explained by the
multiple expressions of other TG genes that may substitute the TG2 missing
isoform, although other TG isoform mutations have been associated to severe
phenotypes, such as lamellar ichthyosis for TG1 isoform mutations.
Bioinformatic studies have shown that the primary structures of human TGs share
some identities in only few regions, such as the active site and the calcium
binding regions. However, high sequence conservation and, therefore, a high
degree of preservation of secondary structure among TG2, TG3 and FXIIIa
indicate that these TGs all share four-domain tertiary structures which could
be similar to those of other TGs[27].
POSSIBLE
ROLES OF THE TRANSGLUTAMINASES IN
NEURODEGENERATIVE DISEASES
Numerous scientific reports suggest that the transglutaminase activity
is involved in the pathogenesis of neurodegenerative diseases, but, to date,
however, also controversial experimental findings about the role of the TGs
enzymes in these diseases have been obtained[28-30]. Protein
aggregates in affected brain regions are histopathological hallmarks of many
neurodegenerative diseases[31]. More than 20 years ago Selkoe et
al[32] suggested that TG activity might contribute to the
formation of protein aggregates in AD brain. In support of this hypothesis, tau
protein has been shown to be an excellent in vitro substrate of TGs[33,34]
and GGEL cross-links have been found in the neurofibrillary tangles and paired
helical filaments of AD brains[35]. Interestingly, a recent work
showed the presence of bis -glutamyl putrescine in human CSF, which was increased in Huntington¡¯s
Disease (HD) CSF[36]. This is an important evidence that
protein/peptides crosslinking by polyamines does indeed occur in brain, and
that this is increased in HD brain. TG activity has been shown to induce also
amyloid -protein
oligomerization[37] and aggregation at physiologic levels[38].
By these molecular mechanisms, TGs could contribute to AD symptoms and
progression[38]. Moreover, there is evidence that TGs also
contribute to the formation of proteinaceous deposits in Parkinson¡¯s Disease
(PD)[39,40], in supranuclear palsy[41,42] and in HD, a
neurodegenerative disease caused by a CAG expansion in the affected gene[43].
For example, expanded polyglutamine domains have been reported to be substrates
of TG2[44-46] and therefore aberrant TG activity could contribute to
CAG-expansion diseases, including HD (Figure 3). However, although all these
studies suggest the possible involvement of the TGs in the formation of
deposits of protein aggregates in neurodegenerative diseases, they do not
indicate whether aberrant TG activity per se directly determines the disease
progression. For example, several experimental findings reported that TG2
activity in vitro leads to the formation of soluble aggregates of -synuclein[47]
or polyQ proteins[48,49]. To date, as previously reported, at least
ten human CAG-expansion diseases have been described (Table 2)[50-59]
and in at least eight of them their neuropathology is caused by the expansion
in the number of residues in the polyglutamine domain to a value beyond 35-40.
Remarkably, the mutated proteins have no obvious similarities except for the
expanded polyglutamine domain. In fact, in all cases except SCA 12, the
mutation occurs in the coding region of the gene. However, in SCA12, the CAG
triplet expansion occurs in the untranslated region at the 5' end of the
PPP2R2B gene. It has been proposed that the toxicity results from
overexpression of the brain specific regulatory subunit of protein phosphatase
PP2A[56]. Most of the mutated proteins are widely expressed both
within the brain and elsewhere in the body. A major challenge then is to
understand why the brain is primarily affected and why different regions within
the brain are affected in the different CAG-expansion diseases, i.e., what
accounts for the neurotoxic gain of function of each protein and for a
selective vulnerability of each cell type. Possibly, the selective
vulnerability[60] may be explained in part by the susceptibility of
the expanded polyglutamine domains in the various CAG-expansion diseases to act
as cosubstrates for a brain TG (Figure 4). To strengthen the possible central
role of the TGs in neurodegenerative diseases, a study by Hadjivassiliou et
al[61] showed that anti-TG2 IgA antibodies are present in the gut
and brain of patients with gluten ataxia, a non-genetic sporadic cerebellar
ataxia, but not in ataxia control patients. Recently, anti-TG2, -TG3 and -TG6
antibodies have been found in sera from CD patients, suggesting a possible
involvement also of other TGs in the pathogenesis of dermatitis herpetiformis
and gluten ataxia, two frequent extra intestinal manifestations of gluten
sensitivity[62,63].
In support to the hypothesis of the
toxic effect of TG activity in other neurodegenerative diseases, such as
Alzheimer¡¯s disease and Parkinson¡¯s Disease, TG activity has been shown to
induce amyloid beta-protein and -synuclein oligomerization and aggregation at physiologic levels[64-66].
In fact, TG activity induces protofibril-like amyloid beta-protein assemblies
that are protease-resistant and inhibit long-term potentiation[38].
Therefore, by these molecular mechanisms, TG activity could also contribute to
Alzheimer's disease symptoms and progression. Finally, a recent work by Basso et
al[67] found that in addition to TG2, TG1 gene expression level
is significantly induced following stroke in vivo or due to oxidative
stress in vitro. Moreover, structurally diverse inhibitors, used at
concentrations that inhibit TG1 and TG2 simultaneously, are neuroprotective.
Together, these last studies suggested that multiple TG isoforms, not only TG2,
participate in oxidative stress-induced cell death signalling, and that isoform
nonselective inhibitors of TG will be most efficacious in combating oxidative
death in neurological disorders. These are interesting and worthwhile studies,
suggesting that multiple TG isoforms can participate in neuronal death
processes. Therefore, all these studies suggest that the involvement of brain
TGs could represent a common denominator in several neurological diseases,
which can lead to the determination of pathophysiological consequences through
different molecular mechanisms.
TRANSGLUTAMINASE
INHIBITION AS POSSIBLE THERAPEUTICAL
APPROACH
In consideration to the fact that up to now there have been no
long-term effective treatments for the human neurodegenerative diseases
previously reported, then the possibility that selective TG inhibitors may be
of clinical benefit has been seriously considered. In this respect, some
encouraging results have been obtained with TG inhibitors in preliminary
studies with different biological models of CAG-expansion diseases. For
example, cystamine (Figure 5), is a potent in vitro inhibitor of enzymes that require
an unmodified cysteine at the active site[68]. Inasmuch as TGs
contain a crucial active-site cysteine, cystamine has the potential to inhibit
these enzymes by a sulfide-disulfide interchange reaction. A sulfide-disulfide
interchange reaction results in the formation of cysteamine and a
cysteamine-cysteine mixed disulfide residue at the active site. Recent studies
have shown that cystamine decreases the number of protein inclusions in
transfected cells expressing the atrophin (DRPLA) protein containing a
pathological-length polyglutamine domain[69]. In other studies,
cystamine administration to HD-transgenic mice resulted in an increase in life
expectancy and amelioration of neurological symptoms[70,71].
Neuronal inclusions were decreased in one of these studies[71].
Although all these scientific reports seem to support the hypothesis of a
direct role of transglutaminase activity in the pathogenesis of the
polyglutamine diseases, cystamine is also found to act in the HD-transgenic
mice by mechanisms other than the inhibition of TGs, such as the inhibition of
caspases[72], suggesting that this compound can have an additive
effect in the therapy of HD. Currently, cysteamine is already in phase I
studies in humans with HD[73], but several side effects, such as
nausea, motor impairment and dosing schedule have been reported as reasons for
non-adherence during phase II studies in human patients affected by cystinosis[74,75].
Another critical problem in the use of TG inhibitors in treating neurological
diseases relates to the fact that, as previously reported, the human brain
contains at least four TGs, including TG1, 2, 3[22] and TG6[76],
and a strong non-selective inhibitor of TGs might also inhibit plasma Factor
XIIIa, causing a bleeding disorder. Therefore, from a number of standpoints it
would seem that a selective inhibitor, which discriminates between TGs, would
be preferable to an indiscriminate TG inhibitor. In fact, although most of the
TG activity in mouse brain, at least as assessed by an assay that measures the
incorporation of radioactive putrescine (amine donor) into N,N-dimethyl casein
(amine acceptor), seems to be due to TG2[77], no conclusive data
have been obtained by TG2 gene knock-out experiments about the involvement of
this TG in the development of the symptoms in HD-transgenic mice[26,78,79].
Moreover, a recent scientific report showed that cystamine reduces aggregate
formation in a mouse model of oculopharyngeal muscular dystrophy (OMPD), in
which also the TG2 knockdown is capable of suppressing the aggregation and the
toxicity of the mutant protein PABPN1[80], suggesting this compound
as a possible therapeutic for OMPD.
CONCLUSIONS
In conclusion, numerous scientific reports have implicated aberrant TG
activity in neurodegenerative diseases, but still today we are looking for
experimental findings which could definitely confirm the direct involvement of TGs in the pathogenetic
mechanisms responsible for these diseases. However, as result of the putative
role of specific TG isoforms, such as TG2, in some human diseases, there is a
considerable interest in developing inhibitors of these enzymes. Of those
currently available, cystamine is the most commonly used experimentally to
inhibit TG2 activity. In addition to cystamine, several types of TG2 inhibitors
have been developed up to now[81]. Interestingly, some of these
inhibitors have shown promising results in experimental diabetic models[82].
Therefore, the use of these inhibitors of TGs could be then useful also for
other clinical approaches. To minimize the possible side effects, however, more
selective inhibitors of the TGs should be required in the future. Progress in
this area of research could be achieved also through pharmaco-genetic
techniques.
Acknowledgements
This work is supported by the Italian Education Department and the
Regione Campania (L.R. n.5 del
28.03.2002, finanziamento 2008).
CONFLICT OF INTERESTS
The Authors have no conflicts of interest to declare.
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Peer reviewer: Qun
Bi, Associate Prof., College of Life Sciences, Peking University, Yiheyuan
Street #5, Beijing 100871, China.
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