You will be presented with the full text of a biomedical research paper. Please write an abstract for this paper. Your response should include the abstract and no additional text.

Paper text:
2.3.2.13 ) are a family of enzymes ( table 1 ) which   catalyze   irreversible posttranslational 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   ( figure 2 ) .   the transamidating activity of tgs is activated by the binding of ca , 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 -amino group of a lysyl residue in a protein / polypeptide , an n-(-l - glutamyl)-l - lysine ( ggel ) isopeptide bond is formed ( figure 1 , example ( a ) ) . on the other hand , if a polyamine or another primary amine ( e.g. , histamine ) acts as the amine donor , a -glutamylpolyamine ( or -glutamylamine ) residue is formed ( figure 1 , example ( b ) ) .
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 .
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 ( c ) ) .
it is worthwhile noting that two of these reactions , in particular , the deamidation of peptides obtained from the digestion of the gliadin , a protein present in wheat , and the   n-(-l - glutamyl)-l - lysine ( ggel ) isopeptide formation between these peptides and  tissue  transglutaminase   ( tg2 or ttg ) , have been recently shown to cause the formation of new antigenic epitopes which are responsible of immunological reactions during the celiac disease ( cd ) , one of the most common human autoimmune diseases [ 4 , 5 ] .  
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 n-(-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 . in some tgs , other catalytic activities , such as the ability to hydrolyze   gtp ( or atp ) into gdp ( or adp ) and inorganic phosphate , a protein disulfide isomerase activity ,
a serine / threonine kinase activity , and an esterification activity , are often present [ 69 ] .
    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 , while other activities , recently identified , could be present .
for example , in some pathophysiological states , when the concentration of ca 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 ca .
gtp and ca regulate its enzymatic activities , including protein cross - linking , in a reciprocal manner ; the binding of ca inhibits gtp - binding and gtp - binding inhibits the transglutaminase cross - linking activity of the tg2 .
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/gh can mediate the activation of   phospholipase c ( plc )   by the 1b - adrenergic receptor   and   can modulate adenylyl cyclase activity .
tg2/gh can also   mediate the activation of   the 1 isoform   of plc and of maxi - k channels .
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 .
evidence of a pathophysiological role of the tgs in cell signaling , in disulfide isomerase activity , and in other biological functions ,   is lacking to date .
     at least eight different tgs ,   distributed in the human body , have been identified ( table 1 ) .
complex mechanisms regulating the gene expression of tgs , both at transcriptional and translational levels , determine a complex but precise distribution of these enzymes in a cell and/or a tissue .
such complex gene expression reflects the physiological roles that these enzymes play in both the intracellular and extracellular compartments . in the nervous system , for example ,
moreover , several alternative splice variants of tgs , mostly in the 3-end region , have been identified .
interestingly , some of them are differently expressed in human pathologies , such as alzheimer 's disease ( ad ) .   on the basis of their ubiquitous expression and their biological roles
however , this does not always seem to be the case , since , for example , null mutants of the tg2 are usually phenotypically normal at birth .
this result may be explained by the multiple expressions of other tg genes that could be substituting the missing isoform .     
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 residue 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 .
       numerous scientific reports suggest that tg activity is involved in the pathogenesis of alzheimer 's disease and other neurodegenerative diseases . to date , however , definitive experimental findings about the role of these enzymes in the development of these neurological diseases have not yet been obtained .
protein aggregates in affected brain regions are histopathological hallmarks of alzheimer 's disease and many other   neurodegenerative diseases .
more than 20 years ago , selkoe et al .    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 [ 2932 ] , and ggel cross - links have been found in the neurofibrillary tangles and paired helical filaments of ad brains [ 33 , 34 ] .
in addition to these experimental findings , it has been shown that tgs and transglutaminase - catalyzed cross - links colocalize with pathological lesions in alzheimer 's disease brain [ 3436 ] .  
interestingly , a recent work showed the presence of bis -glutamyl putrescine in human csf , which was increased in huntington 's disease ( hd ) csf .
these are important experimental data which demonstrate that protein / peptides cross - links and   protein / peptides cross - linking by polyamines do indeed occur in brain , and that these transglutaminase - catalyzed reaction products are increased in ad and hd brains .
more recently , tg activity has been shown to induce amyloid -protein oligomerization   and aggregation at physiologic levels in vitro [ 38 , 39 ] . by these molecular mechanisms
moreover , there is evidence that tgs also contribute to the formation of proteinaceous deposits in parkinson 's disease ( pd ) [ 40 , 41 ] and   in supranuclear palsy [ 42 , 43 ] . to support the role of the tg activity in the pathogenesis of neurodegenerative diseases ,
expanded polyglutamine domains , present    in hd and other   neurodegenerative diseases caused by a cag expansion in the affected gene ( table 2 )   , have been   reported to be substrates of tg2 in vitro [ 4547 ] .
therefore , aberrant tg activity could contribute to the pathogenesis of neurodegenerative diseases , including alzheimer 's disease and other neurodegenerative diseases , by different molecular mechanisms , as described in   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 's progression .   in support of the hypothesis of a pathophysiological role for protein aggregates in neurodegenerative diseases ,
it is worth noting that the aggregate formation has been shown to inhibit the proteasome degradation of expanded polyglutamine proteins .
      since up to now there have been no long - term effective treatments for human neurodegenerative diseases , 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 4 ) is a potent in vitro inhibitor of enzymes that require an unmodified cysteine at the active site .
inasmuch as tgs contain a crucial active - site cysteine , cystamine has the potential to inhibit these enzymes by disulfide interchange reactions .   a 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   protein containing a pathological - length polyglutamine domain , responsible for the dentato - rubro - pallido - luysian atrophy ( drpla ) .  
in other studies , cystamine administration to hd - transgenic mice resulted in an increase in life expectancy and amelioration of neurological symptoms [ 61 , 62 ] .
although all these scientific reports seem to support the hypothesis of a direct role of tg 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 , suggesting that this compound can have an additive effect in the therapy of hd .
the pharmacodynamics and the pharmacokinetics of cystamine , therefore , should be carefully investigated in order to confirm the same effectiveness in patients with neurodegenerative diseases .
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 , and possibly tg6 , and a strong nonselective 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 , no conclusive data has been obtained by tg2 gene knock - out experiments about the involvement of this tg   in the development of the symptoms in hd - transgenic mice .
however , 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 to suppress the aggregation and the toxicity of the mutant protein pabpn1 , suggesting   this compound as a possible therapeutic for ompd .
    although many scientific reports have implicated aberrant tg activity in alzheimer 's disease and other neurodegenerative diseases ,   still today we are looking for data which could definitely confirm   the direct involvement of tgs in the pathogenetic mechanisms responsible for these diseases .  
to minimize the possible side effects , however , selective inhibitors of   the tgs   should be required in the future .
transglutaminases are ubiquitous enzymes which catalyze posttranslational modifications of proteins . recently 
 , transglutaminase - catalyzed post - translational modification of proteins has been shown to be involved in the molecular mechanisms responsible for human diseases . 
 transglutaminase activity has been hypothesized to be involved also in the pathogenetic mechanisms responsible for several human neurodegenerative diseases . 
 alzheimer 's disease and other neurodegenerative diseases , such as parkinson 's disease , supranuclear palsy , huntington 's disease , and other polyglutamine diseases , are characterized in part by aberrant cerebral transglutaminase activity and by increased cross - linked proteins in affected brains . 
 this paper focuses on the possible molecular mechanisms by which transglutaminase activity could be involved in the pathogenesis of alzheimer 's disease and other neurodegenerative diseases , and on the possible therapeutic effects of selective transglutaminase inhibitors for the cure of patients with diseases characterized by aberrant transglutaminase activity .