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Alpha-synuclein and tau: teammates in neurodegeneration?

Moussaud S, Jones DR, Moussaud-Lamodière EL, Delenclos M, Ross OA, McLean PJ - Mol Neurodegener (2014)

Bottom Line: Moreover, tau and α-synuclein appear to promote the fibrillization and solubility of each other in vitro and in vivo.This suggests that interactions between tau and α-synuclein form a deleterious feed-forward loop essential for the development and spreading of neurodegeneration.Here, we review the recent literature with respect to elucidating the possible links between α-synuclein and tau.

View Article: PubMed Central - PubMed

Affiliation: Mayo Clinic Jacksonville, 4500 San Pablo Road, Jacksonville, FL 32224, USA. McLean.Pamela@mayo.edu.

ABSTRACT
The accumulation of α-synuclein aggregates is the hallmark of Parkinson's disease, and more generally of synucleinopathies. The accumulation of tau aggregates however is classically found in the brains of patients with dementia, and this type of neuropathological feature specifically defines the tauopathies. Nevertheless, in numerous cases α-synuclein positive inclusions are also described in tauopathies and vice versa, suggesting a co-existence or crosstalk of these proteinopathies. Interestingly, α-synuclein and tau share striking common characteristics suggesting that they may work in concord. Tau and α-synuclein are both partially unfolded proteins that can form toxic oligomers and abnormal intracellular aggregates under pathological conditions. Furthermore, mutations in either are responsible for severe dominant familial neurodegeneration. Moreover, tau and α-synuclein appear to promote the fibrillization and solubility of each other in vitro and in vivo. This suggests that interactions between tau and α-synuclein form a deleterious feed-forward loop essential for the development and spreading of neurodegeneration. Here, we review the recent literature with respect to elucidating the possible links between α-synuclein and tau.

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Putative pathways of deleterious tau and α-synuclein interactions. Interaction of tau and αsyn may promote pathogenesis via distinct mechanisms. 1. αSyn may block the normal interaction between tau and tubulin by directly binding to tau and tubulin and thereby interfering with tau physiological function. 2. αSyn could recruit kinases and promote the hyperphosphorylation of tau. 3. αSyn may also catalyze tau polymerization and trigger the formation of tau/αsyn co-oligomers. 4. Finally, αsyn oligomers or fibrils may seed tau fibrillization and thereby initiate and propagate tauopathy.
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Fig4: Putative pathways of deleterious tau and α-synuclein interactions. Interaction of tau and αsyn may promote pathogenesis via distinct mechanisms. 1. αSyn may block the normal interaction between tau and tubulin by directly binding to tau and tubulin and thereby interfering with tau physiological function. 2. αSyn could recruit kinases and promote the hyperphosphorylation of tau. 3. αSyn may also catalyze tau polymerization and trigger the formation of tau/αsyn co-oligomers. 4. Finally, αsyn oligomers or fibrils may seed tau fibrillization and thereby initiate and propagate tauopathy.

Mentions: The promotion of tau hyperphosphorylation by αsyn has been demonstrated in several studies and could be a mechanism that explains how αsyn triggers tauopathy (Figure 4). An in vitro study showed that αsyn promotes tau phosphorylation at S262 and S356 residues via PKA [127]. Later, another tau kinase, GSK3β, was found to be recruited and activated in an αsyn-dependent manner and provoke tau hyperphosphorylation at T181, S396, and S404 residues [88, 91, 120, 132]. This effect seems to be the result of both an increase GSK3β kinase activity [91, 105] and the formation of a tripartite GSK3β-αsyn-tau complex with tau binding to the acidic C-terminus of αsyn, and GSK3β to the NAC and KTEGV domains of αsyn [132]. However, it has also been shown that similar to αsyn, β- and γ-synuclein can also induce GSK3β autophosphorylation and that β-synuclein could even promote tau phosphorylation, questioning the specificity of this mechanism and its physiological relevance [132]. Nonetheless other facts reinforce the idea of a link between GSK3β, tau and αsyn. For instance, in a cellular MPTP model, GSK3β inhibition with lithium or TDZD-8 was able to decrease tau phosphorylation but also αsyn accumulation and cell death [91]. However GSK3β is not the only kinase that links αsyn with hyperphosphorylated tau. Indeed, activation of ERK and JNK, that also phosphorylate tau at S396 and S404 residues, correlate with the presence of phospho-tau in αsyn overexpressing transgenic mouse models [102, 106, 107]. In addition, tau phosphorylation at S262 and S356 residues by PKA is exacerbated by αsyn in vitro[127]. Following this, PKA was identified as the responsible kinase for the αsyn-dependent phosphorylation of tau at S262 residue after MPTP treatment in cells [92]. Interestingly, PKA does not phosphorylate tau at S396 and S404 residues, whereas GSK3β does not phosphorylate tau at S262 residue suggesting that both kinases probably have an additive role in the induction of tauopathy by αsyn (Figure 4). Recently, tau has been identified as a putative substrate for the PD-related kinase LRRK2 [133, 134] and genetic correction of the PD-related LRRK2 G2019S mutation in human induced pluripotent stem cells resulted in a decreased tau and αsyn expression [135], linking tau once more to PD.Figure 4


Alpha-synuclein and tau: teammates in neurodegeneration?

Moussaud S, Jones DR, Moussaud-Lamodière EL, Delenclos M, Ross OA, McLean PJ - Mol Neurodegener (2014)

Putative pathways of deleterious tau and α-synuclein interactions. Interaction of tau and αsyn may promote pathogenesis via distinct mechanisms. 1. αSyn may block the normal interaction between tau and tubulin by directly binding to tau and tubulin and thereby interfering with tau physiological function. 2. αSyn could recruit kinases and promote the hyperphosphorylation of tau. 3. αSyn may also catalyze tau polymerization and trigger the formation of tau/αsyn co-oligomers. 4. Finally, αsyn oligomers or fibrils may seed tau fibrillization and thereby initiate and propagate tauopathy.
© Copyright Policy - open-access
Related In: Results  -  Collection

License 1 - License 2
Show All Figures
getmorefigures.php?uid=PMC4230508&req=5

Fig4: Putative pathways of deleterious tau and α-synuclein interactions. Interaction of tau and αsyn may promote pathogenesis via distinct mechanisms. 1. αSyn may block the normal interaction between tau and tubulin by directly binding to tau and tubulin and thereby interfering with tau physiological function. 2. αSyn could recruit kinases and promote the hyperphosphorylation of tau. 3. αSyn may also catalyze tau polymerization and trigger the formation of tau/αsyn co-oligomers. 4. Finally, αsyn oligomers or fibrils may seed tau fibrillization and thereby initiate and propagate tauopathy.
Mentions: The promotion of tau hyperphosphorylation by αsyn has been demonstrated in several studies and could be a mechanism that explains how αsyn triggers tauopathy (Figure 4). An in vitro study showed that αsyn promotes tau phosphorylation at S262 and S356 residues via PKA [127]. Later, another tau kinase, GSK3β, was found to be recruited and activated in an αsyn-dependent manner and provoke tau hyperphosphorylation at T181, S396, and S404 residues [88, 91, 120, 132]. This effect seems to be the result of both an increase GSK3β kinase activity [91, 105] and the formation of a tripartite GSK3β-αsyn-tau complex with tau binding to the acidic C-terminus of αsyn, and GSK3β to the NAC and KTEGV domains of αsyn [132]. However, it has also been shown that similar to αsyn, β- and γ-synuclein can also induce GSK3β autophosphorylation and that β-synuclein could even promote tau phosphorylation, questioning the specificity of this mechanism and its physiological relevance [132]. Nonetheless other facts reinforce the idea of a link between GSK3β, tau and αsyn. For instance, in a cellular MPTP model, GSK3β inhibition with lithium or TDZD-8 was able to decrease tau phosphorylation but also αsyn accumulation and cell death [91]. However GSK3β is not the only kinase that links αsyn with hyperphosphorylated tau. Indeed, activation of ERK and JNK, that also phosphorylate tau at S396 and S404 residues, correlate with the presence of phospho-tau in αsyn overexpressing transgenic mouse models [102, 106, 107]. In addition, tau phosphorylation at S262 and S356 residues by PKA is exacerbated by αsyn in vitro[127]. Following this, PKA was identified as the responsible kinase for the αsyn-dependent phosphorylation of tau at S262 residue after MPTP treatment in cells [92]. Interestingly, PKA does not phosphorylate tau at S396 and S404 residues, whereas GSK3β does not phosphorylate tau at S262 residue suggesting that both kinases probably have an additive role in the induction of tauopathy by αsyn (Figure 4). Recently, tau has been identified as a putative substrate for the PD-related kinase LRRK2 [133, 134] and genetic correction of the PD-related LRRK2 G2019S mutation in human induced pluripotent stem cells resulted in a decreased tau and αsyn expression [135], linking tau once more to PD.Figure 4

Bottom Line: Moreover, tau and α-synuclein appear to promote the fibrillization and solubility of each other in vitro and in vivo.This suggests that interactions between tau and α-synuclein form a deleterious feed-forward loop essential for the development and spreading of neurodegeneration.Here, we review the recent literature with respect to elucidating the possible links between α-synuclein and tau.

View Article: PubMed Central - PubMed

Affiliation: Mayo Clinic Jacksonville, 4500 San Pablo Road, Jacksonville, FL 32224, USA. McLean.Pamela@mayo.edu.

ABSTRACT
The accumulation of α-synuclein aggregates is the hallmark of Parkinson's disease, and more generally of synucleinopathies. The accumulation of tau aggregates however is classically found in the brains of patients with dementia, and this type of neuropathological feature specifically defines the tauopathies. Nevertheless, in numerous cases α-synuclein positive inclusions are also described in tauopathies and vice versa, suggesting a co-existence or crosstalk of these proteinopathies. Interestingly, α-synuclein and tau share striking common characteristics suggesting that they may work in concord. Tau and α-synuclein are both partially unfolded proteins that can form toxic oligomers and abnormal intracellular aggregates under pathological conditions. Furthermore, mutations in either are responsible for severe dominant familial neurodegeneration. Moreover, tau and α-synuclein appear to promote the fibrillization and solubility of each other in vitro and in vivo. This suggests that interactions between tau and α-synuclein form a deleterious feed-forward loop essential for the development and spreading of neurodegeneration. Here, we review the recent literature with respect to elucidating the possible links between α-synuclein and tau.

Show MeSH
Related in: MedlinePlus