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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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Related in: MedlinePlus

Schematic representation of tau and α-synuclein proteins. A- Alternative splicing of the N1, N1 + N2 and R2 regions (white) yields in 6 different tau isoforms referred to as 0N3R (=tau23 or tau-352), 0N4R (=tau24 or tau-383), 1N3R (=tau37 or tau-381), 1N4R (=tau46 or tau-412), 2N3R (=tau39 or tau-410) and 2N4R (=tau40 or tau-441). Tau has an acidic N-terminus and a tubulin binding region where the vast majority of the exonic (▽) and intronic (not depicted here) disease-associated mutations are found. B- αSyn is a 14.5 kDa protein divided into 3 major regions; the amphipathic N-terminus, the hydrophobic Non-Amyloid Component (NAC) domain, and the acidic C-terminus. Pathogenic missense mutations described to date (▽) are located in the N-terminal region, whereas most disease-related phosphorylation sites (▲) are localized to the C-terminal region of the protein.
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Fig2: Schematic representation of tau and α-synuclein proteins. A- Alternative splicing of the N1, N1 + N2 and R2 regions (white) yields in 6 different tau isoforms referred to as 0N3R (=tau23 or tau-352), 0N4R (=tau24 or tau-383), 1N3R (=tau37 or tau-381), 1N4R (=tau46 or tau-412), 2N3R (=tau39 or tau-410) and 2N4R (=tau40 or tau-441). Tau has an acidic N-terminus and a tubulin binding region where the vast majority of the exonic (▽) and intronic (not depicted here) disease-associated mutations are found. B- αSyn is a 14.5 kDa protein divided into 3 major regions; the amphipathic N-terminus, the hydrophobic Non-Amyloid Component (NAC) domain, and the acidic C-terminus. Pathogenic missense mutations described to date (▽) are located in the N-terminal region, whereas most disease-related phosphorylation sites (▲) are localized to the C-terminal region of the protein.

Mentions: Interestingly, at the molecular level, protein misfolding, accumulation, aggregation and subsequently the formation of amyloid deposits are common features in many neurological disorders including AD and PD. Thus neurodegenerative diseases are sometimes referred to as proteinopathies [4]. The existence of a common mechanism suggests that neurodegenerative disorders likely share a common trigger and that the nature of the pathology is determined by the type of the aggregated protein and the localization of the cell affected (Figures 1, 2 and 3).Figure 1


Alpha-synuclein and tau: teammates in neurodegeneration?

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

Schematic representation of tau and α-synuclein proteins. A- Alternative splicing of the N1, N1 + N2 and R2 regions (white) yields in 6 different tau isoforms referred to as 0N3R (=tau23 or tau-352), 0N4R (=tau24 or tau-383), 1N3R (=tau37 or tau-381), 1N4R (=tau46 or tau-412), 2N3R (=tau39 or tau-410) and 2N4R (=tau40 or tau-441). Tau has an acidic N-terminus and a tubulin binding region where the vast majority of the exonic (▽) and intronic (not depicted here) disease-associated mutations are found. B- αSyn is a 14.5 kDa protein divided into 3 major regions; the amphipathic N-terminus, the hydrophobic Non-Amyloid Component (NAC) domain, and the acidic C-terminus. Pathogenic missense mutations described to date (▽) are located in the N-terminal region, whereas most disease-related phosphorylation sites (▲) are localized to the C-terminal region of the protein.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

Fig2: Schematic representation of tau and α-synuclein proteins. A- Alternative splicing of the N1, N1 + N2 and R2 regions (white) yields in 6 different tau isoforms referred to as 0N3R (=tau23 or tau-352), 0N4R (=tau24 or tau-383), 1N3R (=tau37 or tau-381), 1N4R (=tau46 or tau-412), 2N3R (=tau39 or tau-410) and 2N4R (=tau40 or tau-441). Tau has an acidic N-terminus and a tubulin binding region where the vast majority of the exonic (▽) and intronic (not depicted here) disease-associated mutations are found. B- αSyn is a 14.5 kDa protein divided into 3 major regions; the amphipathic N-terminus, the hydrophobic Non-Amyloid Component (NAC) domain, and the acidic C-terminus. Pathogenic missense mutations described to date (▽) are located in the N-terminal region, whereas most disease-related phosphorylation sites (▲) are localized to the C-terminal region of the protein.
Mentions: Interestingly, at the molecular level, protein misfolding, accumulation, aggregation and subsequently the formation of amyloid deposits are common features in many neurological disorders including AD and PD. Thus neurodegenerative diseases are sometimes referred to as proteinopathies [4]. The existence of a common mechanism suggests that neurodegenerative disorders likely share a common trigger and that the nature of the pathology is determined by the type of the aggregated protein and the localization of the cell affected (Figures 1, 2 and 3).Figure 1

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