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 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.
Szodorai
Anita
A
Technical University of Kaiserslautern, Department of Human Biology and Human Genetics, D-67663 Kaiserslautern, Germany.
Kuan
Yung-Hui
YH
Hunzelmann
Silke
S
Engel
Ulrike
U
Sakane
Ayuko
A
Sasaki
Takuya
T
Takai
Yoshimi
Y
Kirsch
Joachim
J
Müller
Ulrike
U
Beyreuther
Konrad
K
Brady
Scott
S
Morfini
Gerardo
G
Kins
Stefan
S
D016564:Amyloid beta-Protein Precursor / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D001483:Base Sequence; D045744:Cell Line, Tumor; D004789:Enzyme Activation / Q000235:genetics; D020558:GTP Phosphohydrolases / Q000235:genetics / Q000378:metabolism; D006801:Humans; D016547:Kinesins / Q000737:chemistry / Q000378:metabolism / Q000502:physiology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008969:Molecular Sequence Data; D021381:Protein Transport / Q000502:physiology; D022161:Transport Vesicles / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D020826:rab3A GTP-Binding Protein / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*
D016564:Amyloid beta-Protein Precursor; D020558:GTP Phosphohydrolases; D016547:Kinesins; D020826:rab3A GTP-Binding Protein