Syntaxins 6 and 8 facilitate tau into secretory pathways

Lee, Wei Siang; Tan, Daniel C. S.; Deng, Yuanyuan; Hummel, Annika van; Ippati, Stefania; Stevens, Claire H.; Carmona-Mora, Paulina; Ariawan, A. Daryl; Hou, Liming; Stefen, Holly; Tomanic, Tamara; Bi, Mian; Tomasetig, Florence; Martin, Adam D.; Fath, Thomas; Palmer, Steve; Ke, Yazi D.; Ittner, Lars M.

doi:10.1042/bcj20200664

Cited by 8 publications

(9 citation statements)

References 39 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…By TIRF microscopy, we observed a depletion of Tau in the cytoplasm upon the fusion of VAMP8-positive vesicles with the plasma membrane ( Pilliod et al, 2020 ). Other proteins involved in the endocytic pathways such as Bin1 and the two SNAREs, syntaxins 6 and 8 also contribute to Tau secretion ( Glennon et al, 2020 ; Lee et al, 2021 ). It seems possible that each of these pathways could permit the release of a specific set of Tau forms.…”

Section: Discussionmentioning

confidence: 99%

“…Interestingly, polymorphisms associated with Bin1 is the second largest genetic risk for sporadic AD ( Lambert et al, 2013 ; Vardarajan et al, 2015 ). Syntaxins 6 and 8, two SNAREs that play an important role in the membranes trafficking, can interact with Tau C-terminal and increase its secretion ( Lee et al, 2021 ). Syntaxin 6 is found at the trans-Golgi network and early endosomes whereas syntaxin 8 is localized on recycling and late endosomes ( Jung et al, 2012 ).…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Unconventional secretion of tau by VAMP8 impacts its intra- and extracellular cleavage

Pilliod

Gélinas-Faucher

Leclerc

2022

Front. Cell Dev. Biol.

View full text Add to dashboard Cite

In Alzheimer’s disease, Tau, a microtubule-associated protein, becomes hyperphosphorylated, detaches from microtubules, and accumulates in the somato-dendritic compartment where it forms insoluble aggregates. Tau also accumulates in the CSF of patients indicating that it is released by neurons. Consistent with this, several laboratories including ours have shown that Tau is secreted by neurons through unconventional secretory pathways. Recently, we reported that VAMP8, an R-SNARE found on late endosomes, increased Tau secretion and that secreted Tau was cleaved at the C-terminal. In the present study, we examined whether the increase of Tau secretion by VAMP8 affected its intra- and extracellular cleavage. Upon VAMP8 overexpression, an increase of Tau cleaved by caspase-3 in the cell lysate and medium was observed. This was correlated to an increase of active caspase-3 in the cell lysate and medium. Using a Tau mutant not cleavable by caspase-3, we demonstrated that Tau cleavage by caspase-3 was not necessary for its secretion upon VAMP8 overexpression. By adding recombinant Tau to the culture medium, we demonstrated that extracellular Tau cleavage by caspase-3 could occur because of the release of active caspase-3, which was the highest when VAMP8 was overexpressed. When cleavage of Tau by caspase-3 was prevented by using a non-cleavable mutant, secreted Tau was still cleaved at the C-terminal, the asparagine N410 contributing to it. Lastly, we demonstrated that N-terminal of Tau regulated the secretion pattern of a Tau fragment containing the microtubule-binding domain and the C-terminal of Tau upon VAMP8 overexpression. Collectively, the above observations indicate that VAMP8 overexpression affects the intra- and extracellular cleavage pattern of Tau.

show abstract

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Unconventional secretion of tau by VAMP8 impacts its intra- and extracellular cleavage

Pilliod

Gélinas-Faucher

Leclerc

2022

Front. Cell Dev. Biol.

View full text Add to dashboard Cite

show abstract

“…In the latest article by Lee et al [15], yet another fascinating cell exiting strategy was proposed. The authors began their investigation with the intention to better understand the functions of the conserved C-terminal tail region (CTTR) of tau, whose abnormal hyperphosphorylation and aggregation could lead to neurofibrillary tangle (NFT) formation, a trademark of Alzheimer's disease [14].…”

Section: Commentarymentioning

confidence: 99%

Smuggle tau through a secret(ory) pathway

2021

Biochemical Journal

View full text Add to dashboard Cite

Secretion of misfolded tau, a microtubule-binding protein enriched in nerve cells, is linked to the progression of tau pathology. However, the molecular mechanisms underlying tau secretion are poorly understood. Recent work by Lee et al. [Biochemical J. (2021) 478: 1471–1484] demonstrated that the transmembrane domains of syntaxin6 and syntaxin8 could be exploited for tau release, setting a stage for testing a novel hypothesis that has profound implications in tauopathies (e.g. Alzheimer's disease, FTDP-17, and CBD/PSP) and other related neurodegenerative diseases. The present commentary highlights the importance and limitations of the study, and discusses opportunities and directions for future investigations.

show abstract

“…The association of tau with exosomes (Wang et al, 2017), synaptic vesicles (McInnes et al, 2018; Zhou et al, 2017) as well as the soluble N-ethylmaleimide-sensitive factor attachment protein receptor (SNARE) proteins (Lee et al, 2021; Pilliod et al, 2020; Tracy et al, 2022; Xu, 2021) suggests that the neuronal spreading of tau may be dependent on the integrity of synaptic SNAREs, such as syntaxin, 25 kDa synaptosomal-associated protein (SNAP25) and vesicle-associated membrane protein (VAMP)/synaptobrevin. Interestingly, these proteins can be selectively impaired by clostridial neurotoxin (CNT) family, which comprises tetanus neurotoxin (TeNT) and several botulinum neurotoxins (BoNTs).…”

Section: Introductionmentioning

confidence: 99%

Botulinum neurotoxin A modulates the axonal release of pathological tau in hippocampal neurons

Panzi

Lazo²,

Surana

et al. 2023

Preprint

View full text Add to dashboard Cite

Pathological tau aggregates propagate across functionally connected neuronal networks in human neurodegenerative pathologies, such as Alzheimer's disease. However, the mechanism underlying this process is poorly understood. Several studies have showed that tau release is dependent on neuronal activity and that pathological tau is found in the extracellular space in free form, as well as in the lumen of extracellular vesicles. We recently showed that metabotropic glutamate receptor activity and the SNAP25 integrity modulate the release of pathological tau from human and mouse synaptosomes. Here, we have leveraged botulinum neurotoxins (BoNTs), which impair neurotransmitter release by cleaving specific synaptic SNARE proteins, to dissect molecular mechanisms related to tau release at synapses. In particular, we have tested the effect of botulinum neurotoxin A (BoNT/A) on the synaptic release of tau in primary mouse neurons. Hippocampal neurons were grown in microfluidic chambers and transduced with lentiviruses expressing human tau (hTau). We found that neuronal stimulation significantly increases the release of mutant hTau, whereas wild-type hTau is unaffected. Importantly, BoNT/A blocks mutant hTau release, indicating that this process is modulated by SNAP25 in intact neurons. These results suggest that BoNTs are potent tools to study the spreading of pathological proteins in neurodegenerative diseases and will play a central role in identifying novel molecular targets for the development of therapeutic interventions to treat tauopathies.

show abstract

Syntaxins 6 and 8 facilitate tau into secretory pathways

Cited by 8 publications

References 39 publications

Unconventional secretion of tau by VAMP8 impacts its intra- and extracellular cleavage

Unconventional secretion of tau by VAMP8 impacts its intra- and extracellular cleavage

Smuggle tau through a secret(ory) pathway

Botulinum neurotoxin A modulates the axonal release of pathological tau in hippocampal neurons

Contact Info

Product

Resources

About