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Review
. 2024 Apr;19(4):855-862.
doi: 10.4103/1673-5374.382231.

Pathological and physiological functional cross-talks of α-synuclein and tau in the central nervous system

Mingyue Jin  1 , Shengming Wang  2 , Xiaodie Gao  3 , Zhenyou Zou  4 , Shinji Hirotsune  2 , Liyuan Sun  3
Affiliations
Review

Pathological and physiological functional cross-talks of α-synuclein and tau in the central nervous system

Mingyue Jin et al. Neural Regen Res. 2024 Apr.

Abstract

α-Synuclein and tau are abundant multifunctional brain proteins that are mainly expressed in the presynaptic and axonal compartments of neurons, respectively. Previous works have revealed that intracellular deposition of α-synuclein and/or tau causes many neurodegenerative disorders, including Alzheimer's disease and Parkinson's disease. Despite intense investigation, the normal physiological functions and roles of α-synuclein and tau are still unclear, owing to the fact that mice with knockout of either of these proteins do not present apparent phenotypes. Interestingly, the co-occurrence of α-synuclein and tau aggregates was found in post-mortem brains with synucleinopathies and tauopathies, some of which share similarities in clinical manifestations. Furthermore, the direct interaction of α-synuclein with tau is considered to promote the fibrillization of each of the proteins in vitro and in vivo. On the other hand, our recent findings have revealed that α-synuclein and tau are cooperatively involved in brain development in a stage-dependent manner. These findings indicate strong cross-talk between the two proteins in physiology and pathology. In this review, we provide a summary of the recent findings on the functional roles of α-synuclein and tau in the physiological conditions and pathogenesis of neurodegenerative diseases. A deep understanding of the interplay between α-synuclein and tau in physiological and pathological conditions might provide novel targets for clinical diagnosis and therapeutic strategies to treat neurodegenerative diseases.

Keywords: alpha-synuclein; microtubule-associated protein; neurodegenerative disease; tau.

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Conflict of interest statement

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Figures

Figure 1
Figure 1
Structural features of αSyn and tau proteins. (A) Schematic illustration of αSyn. αSyn is comprised of 140 aa and structurally subdivided into three regions: an N-terminal amphipathic region (1–60 aa), a central hydrophobic nonamyloid-β component (NAC) region (61–95 aa) and a highly acidic C-terminal region (96–140 aa). Seven repeats of the lipid-binding motif (XKTKEGVXXXX) consisted of 11 aa involved in the interaction with lipid membrane. PD causing point mutations is mainly located in the N-terminus, three posttranslational modification (PTM) residues located in the C-terminus. (B) Schematic illustration of tau isoforms. Tau protein is comprised of an N-terminal projection domain, a central MT-binding domain and a C-terminal tail. The alternative splicing of E2, E3 and E10 generates six human tau isoforms. According to the N-terminal inserts encoded by E2 and E3, and the C-terminal insert encoded by E10, tau isoforms can be divided in 2N4R, 1N4R, 0N4R, 2N3R, 1N3R, and 0N3R.
Figure 2
Figure 2
Physiological and pathological functions of αSyn and tau in central nervous system. (A) Physiological and pathological functions of αSyn and tau. Both αSyn and tau are neuronal microtubule-associated proteins highly expressed in presynaptic terminals and axonal compartments, respectively. While αSyn mainly involves in neurotransmitter release and reuptake, tau promotes microtubule (MT) assembly and stability in the axon. Emergence of protein oligomers or aggregates disturbs signal transduction and axonal transport regulated by αSyn and tau, producing neurotoxicity and neuronal cell damages. (B) Cooperative function of αSyn and tau during corticogenesis. In the early embryonic stage, αSyn and tau participate in neurogenesis via regulating Notch signaling and MT dynamics. αSyn and tau are tightly maintenance of neuroprogenitor pool during neurogenesis to ensure following gliogenesis in the later embryonic stage. RGC: Radial glial cell; αSyn: α-synuclein.
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References

    1. Alim MA, Ma QL, Takeda K, Aizawa T, Matsubara M, Nakamura M, Asada A, Saito T, Kaji H, Yoshii M, Hisanaga S, Uéda K. Demonstration of a role for alpha-synuclein as a functional microtubule-associated protein. J Alzheimers Dis. 2004;6:435–449. - PubMed
    1. Alonso AC, Zaidi T, Grundke-Iqbal I, Iqbal K. Role of abnormally phosphorylated tau in the breakdown of microtubules in Alzheimer disease. Proc Natl Acad Sci U S A. 1994;91:5562–5566. - PMC - PubMed
    1. Alonso A, Zaidi T, Novak M, Grundke-Iqbal I, Iqbal K. Hyperphosphorylation induces self-assembly of tau into tangles of paired helical filaments/straight filaments. Proc Natl Acad Sci U S A. 2001;98:6923–6928. - PMC - PubMed
    1. Anderson JP, Walker DE, Goldstein JM, de Laat R, Banducci K, Caccavello RJ, Barbour R, Huang J, Kling K, Lee M, Diep L, Keim PS, Shen X, Chataway T, Schlossmacher MG, Seubert P, Schenk D, Sinha S, Gai WP, Chilcote TJ. Phosphorylation of Ser-129 is the dominant pathological modification of alpha-synuclein in familial and sporadic Lewy body disease. J Biol Chem. 2006;281:29739–29752. - PubMed
    1. Arima K, Mizutani T, Alim MA, Tonozuka-Uehara H, Izumiyama Y, Hirai S, Uéda K. NACP/alpha-synuclein and tau constitute two distinctive subsets of filaments in the same neuronal inclusions in brains from a family of parkinsonism and dementia with Lewy bodies: double-immunolabeling fluorescence and electron microscopic studies. Acta Neuropathol. 2000;100:115–121. - PubMed

Grants and funding

Funding: This work was supported by the Natural Science Foundation of Guangxi Zhuang Autonomous Region, Nos. 2022GXNSFAA035622 (to MJ), 2020GXNSFAA297048 (to ZZ); the National Natural Science Foundation of China, No. 82060268 (to ZZ).

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