Abstract
Tau is a microtubule-associated protein with an intrinsically unstructured conformation. Tau is subjected to several pathological post-translational modifications (PTMs), leading to its loss of interaction with microtubules and accumulation as neurofibrillary tangles (NFTs) in neurons. Tau aggregates impede functions of endoplasmic reticulum and mitochondria leading to the generation of oxidative stress and in turn amplifying the Tau aggregation. Tau is channelled to chaperones for folding into their native form, which otherwise causes its degradation and clearance. Cellular response triggers the activation of ubiquitin–proteasome system or autophagy to facilitate Tau degradation, based on the PTMs or mutations associated with Tau. Further, autophagy can be selective where Hsc70 interacts with Tau in monomeric, oligomeric and aggregated form and drives its clearance by chaperone-mediated autophagy pathway (CMA). Lysosome-associated membrane proteins-2A (LAMP-2A) is the key player of CMA that recognises Hsc70-Tau complex and triggers the downstream cascade. Thus, it becomes challenging for mutant Tau to be cleared by CMA as it loses its affinity for Hsc70 and LAMP-2A. In such a scenario, Tau might be degraded by macroautophagy otherwise sequestered by aggresomes. Henceforth, the degradation of Tau and its blockage that is associated with various PTMs of Tau would explain the dynamics of Tau degradation or accumulation in AD. Further, unveiling the role of accessory proteins involved in these degradation pathways would help in understanding their loss of function and preventing Tau clearance.
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Abbreviations
- AD:
-
Alzheimer’s disease
- Atg:
-
Autophagy-related proteins
- BAG:
-
BCL2-associated athanogene
- Bip:
-
Binding immunoglobulin protein
- CHIP:
-
Carboxyl terminus of the Hsc70-interacting protein
- CMA:
-
Chaperone-mediated autophagy
- Drp1:
-
Dynamin-like protein 1
- ER:
-
Endoplasmic reticulum
- ERAD:
-
Endoplasmic reticulum-associated degradation
- GSK-3β:
-
Glycogen synthase kinase-3 β
- IDP:
-
Intrinsically disordered protein
- HSF1:
-
Heat shock factor 1
- LAMP-2A:
-
Lysosome-associated membrane proteins-2A
- LC3B:
-
Microtubule-associated proteins 1A/1B light chain 3B
- NFTs:
-
Neurofibrillary tangles
- PTMs:
-
Post-translational modifications
- ROS:
-
Reactive oxygen species
- UPS:
-
Ubiquitin–proteasome system
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This project is supported in part by grant from in-house CSIR-National Chemical Laboratory Grant MLP029526.
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NV and SC prepared the initial draft of the paper. SC conceived the idea of the work, supervised, provided resources and wrote the paper. All authors read and approved the final paper.
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Gorantla, N.V., Chinnathambi, S. Autophagic Pathways to Clear the Tau Aggregates in Alzheimer’s Disease. Cell Mol Neurobiol 41, 1175–1181 (2021). https://doi.org/10.1007/s10571-020-00897-0
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DOI: https://doi.org/10.1007/s10571-020-00897-0