Tetraspanin 6: a pivotal protein of the multiple vesicular body determining exosome release and lysosomal degradation of amyloid precursor protein fragments

Francesc X.  Guix; Ragna  Sannerud; Fedor Berditchevski; Amaia M.  Arranz; Katrien Horré; An Snellinx; Amantha  Thathiah; Takaomi Saido; Takashi  Saito; Rajesh Sundaresan; Michael Overduin; Samir  Kumar-Singh; Enrico  Radaelli; Nikky  Corthout; Julien  Colombelli; Sébastien  Tosi; Sebastian  Munck; Isabel H.  Salas; Wim Annaert; Bart De Strooper

doi:10.1186/s13024-017-0165-0

Tetraspanin 6: a pivotal protein of the multiple vesicular body determining exosome release and lysosomal degradation of amyloid precursor protein fragments

Francesc X. Guix, Ragna Sannerud, Fedor Berditchevski, Amaia M. Arranz, Katrien Horré, An Snellinx, Amantha Thathiah, Takaomi Saido , Takashi Saito, Rajesh Sundaresan, Michael Overduin, Samir Kumar-Singh, Enrico Radaelli, Nikky Corthout, Julien Colombelli, Sébastien Tosi, Sebastian Munck, Isabel H. Salas, Wim Annaert, Bart De Strooper

Cancer and Genomic Sciences

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Abstract

Background
The mechanisms behind Aβ-peptide accumulation in non-familial Alzheimer’s disease (AD) remain elusive. Proteins of the tetraspanin family modulate Aβ production by interacting to γ-secretase.

Methods
We searched for tetraspanins with altered expression in AD brains. The function of the selected tetraspanin was studied in vitro and the physiological relevance of our findings was confirmed in vivo.

Results
Tetraspanin-6 (TSPAN6) is increased in AD brains and overexpression in cells exerts paradoxical effects on Amyloid Precursor Protein (APP) metabolism, increasing APP-C-terminal fragments (APP-CTF) and Aβ levels at the same time. TSPAN6 affects autophagosome-lysosomal fusion slowing down the degradation of APP-CTF. TSPAN6 recruits also the cytosolic, exosome-forming adaptor syntenin which increases secretion of exosomes that contain APP-CTF.

Conclusions
TSPAN6 is a key player in the bifurcation between lysosomal-dependent degradation and exosome mediated secretion of APP-CTF. This corroborates the central role of the autophagosomal/lysosomal pathway in APP metabolism and shows that TSPAN6 is a crucial player in APP-CTF turnover.

Original language	English
Article number	25
Number of pages	21
Journal	Molecular Neurodegeneration
Volume	12
DOIs	https://doi.org/10.1186/s13024-017-0165-0
Publication status	Published - 10 Mar 2017

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Guix, F. X., Sannerud, R., Berditchevski, F., Arranz, A. M., Horré, K., Snellinx, A., Thathiah, A., Saido , T., Saito, T., Sundaresan, R., Overduin, M., Kumar-Singh, S., Radaelli, E., Corthout, N., Colombelli, J., Tosi, S., Munck, S., Salas, I. H., Annaert, W., & De Strooper , B. (2017). Tetraspanin 6: a pivotal protein of the multiple vesicular body determining exosome release and lysosomal degradation of amyloid precursor protein fragments. Molecular Neurodegeneration, 12, Article 25. https://doi.org/10.1186/s13024-017-0165-0

@article{91893598ea50453498f23753ac2d81ae,

title = "Tetraspanin 6: a pivotal protein of the multiple vesicular body determining exosome release and lysosomal degradation of amyloid precursor protein fragments",

abstract = "BackgroundThe mechanisms behind Aβ-peptide accumulation in non-familial Alzheimer{\textquoteright}s disease (AD) remain elusive. Proteins of the tetraspanin family modulate Aβ production by interacting to γ-secretase.MethodsWe searched for tetraspanins with altered expression in AD brains. The function of the selected tetraspanin was studied in vitro and the physiological relevance of our findings was confirmed in vivo.ResultsTetraspanin-6 (TSPAN6) is increased in AD brains and overexpression in cells exerts paradoxical effects on Amyloid Precursor Protein (APP) metabolism, increasing APP-C-terminal fragments (APP-CTF) and Aβ levels at the same time. TSPAN6 affects autophagosome-lysosomal fusion slowing down the degradation of APP-CTF. TSPAN6 recruits also the cytosolic, exosome-forming adaptor syntenin which increases secretion of exosomes that contain APP-CTF.ConclusionsTSPAN6 is a key player in the bifurcation between lysosomal-dependent degradation and exosome mediated secretion of APP-CTF. This corroborates the central role of the autophagosomal/lysosomal pathway in APP metabolism and shows that TSPAN6 is a crucial player in APP-CTF turnover.",

author = "Guix, {Francesc X.} and Ragna Sannerud and Fedor Berditchevski and Arranz, {Amaia M.} and Katrien Horr{\'e} and An Snellinx and Amantha Thathiah and Takaomi Saido and Takashi Saito and Rajesh Sundaresan and Michael Overduin and Samir Kumar-Singh and Enrico Radaelli and Nikky Corthout and Julien Colombelli and S{\'e}bastien Tosi and Sebastian Munck and Salas, {Isabel H.} and Wim Annaert and {De Strooper}, Bart",

year = "2017",

month = mar,

day = "10",

doi = "10.1186/s13024-017-0165-0",

language = "English",

volume = "12",

journal = "Molecular Neurodegeneration",

issn = "1750-1326",

publisher = "BioMed Central",

}

Guix, FX, Sannerud, R, Berditchevski, F, Arranz, AM, Horré, K, Snellinx, A, Thathiah, A, Saido , T, Saito, T, Sundaresan, R, Overduin, M, Kumar-Singh, S, Radaelli, E, Corthout, N, Colombelli, J, Tosi, S, Munck, S, Salas, IH, Annaert, W & De Strooper , B 2017, 'Tetraspanin 6: a pivotal protein of the multiple vesicular body determining exosome release and lysosomal degradation of amyloid precursor protein fragments', Molecular Neurodegeneration, vol. 12, 25. https://doi.org/10.1186/s13024-017-0165-0

TY - JOUR

T1 - Tetraspanin 6

T2 - a pivotal protein of the multiple vesicular body determining exosome release and lysosomal degradation of amyloid precursor protein fragments

AU - Guix, Francesc X.

AU - Sannerud, Ragna

AU - Berditchevski, Fedor

AU - Arranz, Amaia M.

AU - Horré, Katrien

AU - Snellinx, An

AU - Thathiah, Amantha

AU - Saido , Takaomi

AU - Saito, Takashi

AU - Sundaresan, Rajesh

AU - Overduin, Michael

AU - Kumar-Singh, Samir

AU - Radaelli, Enrico

AU - Corthout, Nikky

AU - Colombelli, Julien

AU - Tosi, Sébastien

AU - Munck, Sebastian

AU - Salas, Isabel H.

AU - Annaert, Wim

AU - De Strooper , Bart

PY - 2017/3/10

Y1 - 2017/3/10

N2 - BackgroundThe mechanisms behind Aβ-peptide accumulation in non-familial Alzheimer’s disease (AD) remain elusive. Proteins of the tetraspanin family modulate Aβ production by interacting to γ-secretase.MethodsWe searched for tetraspanins with altered expression in AD brains. The function of the selected tetraspanin was studied in vitro and the physiological relevance of our findings was confirmed in vivo.ResultsTetraspanin-6 (TSPAN6) is increased in AD brains and overexpression in cells exerts paradoxical effects on Amyloid Precursor Protein (APP) metabolism, increasing APP-C-terminal fragments (APP-CTF) and Aβ levels at the same time. TSPAN6 affects autophagosome-lysosomal fusion slowing down the degradation of APP-CTF. TSPAN6 recruits also the cytosolic, exosome-forming adaptor syntenin which increases secretion of exosomes that contain APP-CTF.ConclusionsTSPAN6 is a key player in the bifurcation between lysosomal-dependent degradation and exosome mediated secretion of APP-CTF. This corroborates the central role of the autophagosomal/lysosomal pathway in APP metabolism and shows that TSPAN6 is a crucial player in APP-CTF turnover.

AB - BackgroundThe mechanisms behind Aβ-peptide accumulation in non-familial Alzheimer’s disease (AD) remain elusive. Proteins of the tetraspanin family modulate Aβ production by interacting to γ-secretase.MethodsWe searched for tetraspanins with altered expression in AD brains. The function of the selected tetraspanin was studied in vitro and the physiological relevance of our findings was confirmed in vivo.ResultsTetraspanin-6 (TSPAN6) is increased in AD brains and overexpression in cells exerts paradoxical effects on Amyloid Precursor Protein (APP) metabolism, increasing APP-C-terminal fragments (APP-CTF) and Aβ levels at the same time. TSPAN6 affects autophagosome-lysosomal fusion slowing down the degradation of APP-CTF. TSPAN6 recruits also the cytosolic, exosome-forming adaptor syntenin which increases secretion of exosomes that contain APP-CTF.ConclusionsTSPAN6 is a key player in the bifurcation between lysosomal-dependent degradation and exosome mediated secretion of APP-CTF. This corroborates the central role of the autophagosomal/lysosomal pathway in APP metabolism and shows that TSPAN6 is a crucial player in APP-CTF turnover.

U2 - 10.1186/s13024-017-0165-0

DO - 10.1186/s13024-017-0165-0

M3 - Article

SN - 1750-1326

VL - 12

JO - Molecular Neurodegeneration

JF - Molecular Neurodegeneration

M1 - 25

ER -

Tetraspanin 6: a pivotal protein of the multiple vesicular body determining exosome release and lysosomal degradation of amyloid precursor protein fragments

Abstract

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