Tissue transglutaminase-induced aggregation of α-synuclein: Implications for Lewy body formation in Parkinson's disease and dementia with Lewy bodies

Junn, Eunsung; Ronchetti, Ruben; Quezado, Martha; Kim, Soo-Youl; Mouradian, M. Maral

doi:10.1073/pnas.0438021100

Cited by 236 publications

(185 citation statements)

References 63 publications

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“…For example, several experimental findings reported that TG2 activity in vitro leads to the formation of soluble aggregates of a-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][51][52][53][54][55][56][57][58][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][36][37][38][39][40]. Remarkably, the mutated proteins have no obvious similarities except for the expanded polyglutamine domain.…”

Section: Role Of the Transglutaminases In Neurodegenerative Diseasesmentioning

confidence: 71%

“…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][45][46] and therefore aberrant TG activity could contribute to CAG-expansion diseases, including HD (Figure 3).…”

Section: Role Of the Transglutaminases In Neurodegenerative Diseasesmentioning

confidence: 99%

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Transglutaminase Activity as a Possible Molecular Mechanism in the Etiopathogenesis of Neurodegenerative Diseases

Gatta¹,

Cammarota²,

Iannaccone³

et al. 2016

Journal of Biochemistry and Molecular Biology Research

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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 therapeutic effects of transglutaminase inhibitors for patients with diseases characterized by aberrant transglutaminase activity. BIOCHEMISTRY OF THE TRANSGLUTAMINASESTransglutaminases (TGs, E.C. 2.3.2.13) are family of Ca 2+ -dependent enzymes which catalyze post-translational modifications of proteins. Examples of TG-catalyzed reactions include: (1) acyl transfer between the g-carboxamide group of a protein/polypeptide glutaminyl residue and the e-amino group of a protein/polypeptide lysyl residue; (2) attachment of a polyamine to the g-carboxamide of a glutaminyl residue; (3) deamidation of the g-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 ABSTRACTTransglutaminases are a family of Ca 2+ -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 -OH 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 and pathological processes. In particular, transglutaminase activity has been shown to be

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Section: Role Of the Transglutaminases In Neurodegenerative Diseasesmentioning

confidence: 71%

Section: Role Of the Transglutaminases In Neurodegenerative Diseasesmentioning

confidence: 99%

Transglutaminase Activity as a Possible Molecular Mechanism in the Etiopathogenesis of Neurodegenerative Diseases

Gatta¹,

Cammarota²,

Iannaccone³

et al. 2016

Journal of Biochemistry and Molecular Biology Research

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“…This finding has broad implications for pathological neuronal function and degeneration because it links TG2 functions in cellular differentiation, cellular stress, and inflammation (34,35) to the chronic defects in Ca 2+ signaling. Numerous literatures have demonstrated that TG2 is up-regulated in various diseases including HD (49, 54, 55, 59-61), AD (37,38,40,42,43,45), and PD (39,44). The splicing mechanism (67, 68) and stress-dependent inductions (34,35,(69)(70)(71)(72) are considered to elucidate the up-regulation, and the increased Ca 2+ levels observed in many diseases (4,(17)(18)(19)(20)(21)(22) are also competent to trigger TG2 activation.…”

Section: Discussionmentioning

confidence: 99%

“…TG type 2 (TG2) is a Ca 2+ -dependent enzyme with widespread distribution and is highly inducible by various stimulations such as oxidative stress, cytokines, growth factors, and retinoic acid (RA) (34,35). TG2 is considered a significant disease-modifying factor in neurodegenerative diseases including HD, AD, and Parkinson's diseases (PD) (34,(36)(37)(38)(39)(40)(41)(42)(43)(44)(45) because TG2 might enzymatically stabilize aberrant aggregates of proteins implicated in these diseases-that is, mutant Htt, β-amyloid, and α-synuclein; however, the causal role of TG2 in Ca 2+ signaling in brain pathogenesis has been unclear. Ablation of TG2 in HD mouse models is associated with increased lifespan and improved motor function (46,47).…”

Section: Significancementioning

confidence: 99%

Aberrant calcium signaling by transglutaminase-mediated posttranslational modification of inositol 1,4,5-trisphosphate receptors

Hamada

Terauchi

Nakamura

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

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The inositol 1,4,5-trisphosphate receptor (IP 3 R) in the endoplasmic reticulum mediates calcium signaling that impinges on intracellular processes. IP 3 Rs are allosteric proteins comprising four subunits that form an ion channel activated by binding of IP 3 at a distance. Defective allostery in IP 3 R is considered crucial to cellular dysfunction, but the specific mechanism remains unknown. Here we demonstrate that a pleiotropic enzyme transglutaminase type 2 targets the allosteric coupling domain of IP 3 R type 1 (IP 3 R1) and negatively regulates IP 3 R1-mediated calcium signaling and autophagy by locking the subunit configurations. The control point of this regulation is the covalent posttranslational modification of the Gln2746 residue that transglutaminase type 2 tethers to the adjacent subunit. Modification of Gln2746 and IP 3 R1 function was observed in Huntington disease models, suggesting a pathological role of this modification in the neurodegenerative disease. Our study reveals that cellular signaling is regulated by a new mode of posttranslational modification that chronically and enzymatically blocks allosteric changes in the ligand-gated channels that relate to disease states.L igand-gated ion channels function by allostery that is the regulation at a distance; the allosteric coupling of ligand binding with channel gating requires reversible changes in subunit configurations and conformations (1). Inositol 1,4,5-trisphosphate receptors (IP 3 Rs) are ligand-gated ion channels that release calcium ions (Ca 2+ ) from the endoplasmic reticulum (ER) (2, 3). IP 3 Rs are allosteric proteins comprising four subunits that assemble a calcium channel with fourfold symmetry about an axis perpendicular to the ER membrane. The subunits of three IP 3 R isoforms (IP 3 R1, IP 3 R2, and IP 3 R3) are structurally divided into three domains: the IP 3 -binding domain (IBD), the regulatory domain, and the channel domain (3-6). Fitting of the IBD X-ray structures (7, 8) to a cryo-EM map (9) indicates that the IBD activates a remote Ca 2+ channel by allostery (8); however, the current X-ray structure only spans 5% of each tetramer, such that the mechanism underlying allosteric coupling of the IBD to channel gating remains unknown.The IP 3 R in the ER mediates intracellular calcium signaling that impinges on homeostatic control in various subsequent intracellular processes. Deletion of the genes encoding the type 1 IP 3 R (IP 3 R1) leads to perturbations in long-term potentiation/ depression (3, 10, 11) and spinogenesis (12), and the human genetic disease spinocerebellar ataxia 15 is caused by haploinsufficiency of the IP 3 R1 gene (13-15). Dysregulation of IP 3 R1 is also implicated in neurodegenerative diseases including Huntington disease (HD) (16-18) and Alzheimer's disease (AD) (19)(20)(21)(22). IP 3 Rs also control fundamental cellular processes-for example, mitochondrial energy production (23, 24), autophagy regulation (24-27), ER stress (28), hepatic gluconeogenesis (29), pancreatic exocytosis (30), and macrophag...

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“…The chaperone heat-shock protein 70 (Hsp70) strongly inhibits ␣-synuclein fibril formation via preferential binding to prefibrillar species. 65 Several compounds can suppress the toxicity of ␣-synuclein, such as ␤-synuclein, inhibitors of tissue transglutaminase, 66 ribozymes, ␣-synuclein siRNAi, 67 and ␣-synuclein antibody. 68 Some of these also represent candidate genes suitable for neuroprotective gene therapy for PD.…”

Section: Gene Therapy For Parkinson's Disease (Pd)mentioning

confidence: 99%

Advances in Gene Therapy for Movement Disorders

Mochizuki

Yasuda

Mouradian³

2008

Neurotherapeutics

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Summary:After nearly 20 years of preclinical experimentation with various gene delivery approaches in animal models of Parkinson's disease (PD), clinical trials are finally underway. The risk/benefit ratio for these procedures is now generally considered acceptable under approved protocols. The current vehicle for gene delivery to the human brain is recombinant adeno-associated viral vector, which is nonpathogenic and non-self-amplifying. Candidate genes tested in PD patients encode 1) glutamic acid decarboxylase, which is injected into the subthalamic nucleus to catalyze biosynthesis of the inhibitory neurotransmitter ␥-aminobutyric acid and so essentially mimic deep brain stimulation of this nucleus; 2) aromatic Lamino acid decarboxylase, which converts L-dopa to dopamine; and 3) neurturin, a member of the glial cell line-derived neurotrophic factor family. Unraveling the genetic underpinnings of PD could allow gene therapy to go beyond modulating neurotransmission or providing trophic effects to dopaminergic neurons by delivering a specific missing or defective gene. For example, the parkin gene (PARK2) is linked to recessively inherited PD due to loss of function mutations; it prevents ␣-synuclein-induced degeneration of nigral dopaminergic neurons in rats and nonhuman primates. On the other hand, for dominantly inherited Huntington's disease (HD), in which an expanded polyglutamine tract imparts to the protein huntingtin a toxic gain of function, repressing expression of the mutant allele in the striatum using RNA interference technology mitigates pathology and delays the phenotype in a mouse model. Here we review the current state of preclinical and clinical gene therapy studies conducted in PD and HD.

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Tissue transglutaminase-induced aggregation of α-synuclein: Implications for Lewy body formation in Parkinson's disease and dementia with Lewy bodies

Cited by 236 publications

References 63 publications

Transglutaminase Activity as a Possible Molecular Mechanism in the Etiopathogenesis of Neurodegenerative Diseases

Transglutaminase Activity as a Possible Molecular Mechanism in the Etiopathogenesis of Neurodegenerative Diseases

Aberrant calcium signaling by transglutaminase-mediated posttranslational modification of inositol 1,4,5-trisphosphate receptors

Advances in Gene Therapy for Movement Disorders

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