Smuggle tau through a secret(ory) pathway

Abstract

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.

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

“…Although tau is associated with different organelles, including ectosomes ( Dujardin et al, 2014 ), exosomes ( Wang et al, 2017 ) and synaptic vesicles ( McInnes et al, 2018 ), and tau oligomers are transported along axons and dendrites (J. W. Wu et al, 2013 ), the precise mechanisms controlling tau release and re-uptake in neurons are not completely understood ( Xu, 2021 ). Several distinct mechanisms have been suggested for tau secretion, such as active exocytosis and unconventional secretion pathways ( Katsinelos et al, 2018 , 2021 ; Nickel and Rabouille, 2009 ).…”

“…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 members of the clostridial neurotoxin (CNT) family, which comprises tetanus neurotoxin (TeNT) and several botulinum neurotoxins (BoNTs).…”

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

“…Emerging evidence also suggests that this spreading of pathological proteins in neuronal-connected regions is activity-dependent (Pooler et al, 2013;Wu et al, 2016;Yamada et al, 2014). Although tau is associated with different organelles, including ectosomes (Dujardin et al, 2014), exosomes (Wang et al, 2017) and synaptic vesicles (McInnes et al, 2018), and tau oligomers are transported along axons and dendrites (J. W. , the precise mechanisms controlling tau release and reuptake in neurons are not completely understood (Xu, 2021). Several distinct mechanisms have been suggested for tau secretion, such as active exocytosis and unconventional secretion pathways (Katsinelos et al, 2021;Katsinelos et al, 2018;Nickel & Rabouille, 2009).…”

“…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).…”