APP Anterograde Transport Requires Rab3A GTPase Activity for Assembly of the Transport Vesicle

The amyloid precursor protein (APP) is anterogradely transported by conventional kinesin in a distinct transport vesicle, but both the biochemical composition of such a vesicle and the specific kinesin-1 motor responsible for transport are poorly defined. APP may be sequentially cleaved by beta- and...

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Bibliographic Details
Published in:The Journal of neuroscience 2009-11, Vol.29 (46), p.14534-14544
Main Authors: Szodorai, Anita, Kuan, Yung-Hui, Hunzelmann, Silke, Engel, Ulrike, Sakane, Ayuko, Sasaki, Takuya, Takai, Yoshimi, Kirsch, Joachim, Muller, Ulrike, Beyreuther, Konrad, Brady, Scott, Morfini, Gerardo, Kins, Stefan
Format: Article
Language:English
Subjects:
Amyloid beta-Protein Precursor - chemistry
Amyloid beta-Protein Precursor - genetics
Amyloid beta-Protein Precursor - metabolism
Animals
Base Sequence
Cell Line, Tumor
Enzyme Activation - genetics
GTP Phosphohydrolases - genetics
GTP Phosphohydrolases - metabolism
Humans
Kinesin - chemistry
Kinesin - metabolism
Kinesin - physiology
Mice
Mice, Inbred C57BL
Mice, Knockout
Molecular Sequence Data
Protein Transport - physiology
rab3A GTP-Binding Protein - chemistry
rab3A GTP-Binding Protein - genetics
rab3A GTP-Binding Protein - metabolism
Transport Vesicles - chemistry
Transport Vesicles - genetics
Transport Vesicles - metabolism
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Summary:The amyloid precursor protein (APP) is anterogradely transported by conventional kinesin in a distinct transport vesicle, but both the biochemical composition of such a vesicle and the specific kinesin-1 motor responsible for transport are poorly defined. APP may be sequentially cleaved by beta- and gamma-secretases leading to accumulation of beta-amyloid (Abeta) peptides in brains of Alzheimer's disease patients, whereas cleavage of APP by alpha-secretases prevents Abeta generation. Here, we demonstrate by time-lapse analysis and immunoisolations that APP is a cargo of a vesicle containing the kinesin heavy chain isoform kinesin-1C, the small GTPase Rab3A, and a specific subset of presynaptic protein components. Moreover, we report that assembly of kinesin-1C and APP in this vesicle type requires Rab3A GTPase activity. Finally, we show cleavage of APP in transport vesicles by alpha-secretase activity, likely mediated by ADAM10. Together, these data indicate that maturation of APP transport vesicles, including recruitment of conventional kinesin, requires Rab3 GTPase activity.
ISSN:0270-6474
1529-2401
DOI:10.1523/JNEUROSCI.1546-09.2009