Chung D-e, Deng X, Yalamanchili HK, Revelli J-P, Han AL, Tadros B, Richman R, Dias M, AlaviNaini F, Boeynaems S, Hyman BT, Zoghbi HY. The big tau splice isoform resists Alzheimer's-related pathological changes. 2024 Jul 31 10.1101/2024.07.30.605685 (version 1) bioRxiv.
Recommends
Please login to recommend the paper.
Comments
Drexel University College of Medicinr
I was impressed with the quality and importance of this study and with the physiological and clinical implications of the results. It is worth noting that big tau has been understudied, despite indications of its possible relevance to degenerative disorders. There has been a 30-year gap between the original discovery of big tau and recent attention to its potential clinical importance. Many thousands of articles have been published on tau, but only a handful on big tau, with rare mentions of it in textbooks or other biomedical resources.
The new experimental findings strongly support predictions that the elongated projection domain of big tau, generated by exon 4a (with extra 250 amino acids), endows it with protective properties against the toxic misfolding, aggregation, and propagation of lower molecular weight tau that result in degeneration of the cognitive centers of the brain (for a review see Fischer and Baas, 2020). The main clues to this idea have been the long-known localization of big tau to regions of the peripheral and central nervous systems that are relatively resistant to degeneration, such as cranial nerve motor nuclei, the visual system, and cerebellum. Other support came from theoretical models of protein folding and aggregation, and the lack of known phosphorylation sites on the 4a exon which defines big tau. What was missing was in vivo confirmation, data from experimental models of degeneration, as well as supportive data from human tissue. These new findings provide that important new information, raising the potential for developing therapies for neurodegenerative disorders based on a better understanding of the protective properties of big tau.
It is important to emphasize that this is a prepublication manuscript, representing preliminary data that has not been peer-reviewed and is likely to be revised before finally being published. Also, while the implications for therapy are exciting, we are a long way from realizing them.
References:
Fischer I, Baas PW. Resurrecting the Mysteries of Big Tau. Trends Neurosci. 2020 Jul;43(7):493-504. Epub 2020 May 17 PubMed.
View all comments by Itzhak FischerUniversity of Cambridge
This intriguing study shows that big tau has distinct physiological properties compared to the other, better-studied isoforms. The prevailing view that big tau is confined to the periphery is also shown to be incomplete. One question raised by the work is whether big tau suppresses aggregation of the other tau isoforms, or just co-exists as an inert pool alongside the more aggregation-prone versions. It is conceivable that the inclusion of a tau isoform with a higher turnover rate into assemblies would help tip the balance toward aggregate degradation. Modulating tau splicing is suggested as a therapeutic approach, for example through isoform-specific ASOs.
Given that big tau may functionally complement other isoforms, this strategy could offer a safer alternative than global tau knockdown, the long-term effects of which are not clear. A better understanding of how this isoform interacts with aggregates, and its role in neuronal physiology, is very much warranted.
View all comments by William McEwanMake a Comment
To make a comment you must login or register.