Inhibition of Kinesin Synthesis In Vivo Inhibits the Rapid Transport of Representative Proteins for Three Transport Vesicle Classes into the Axon

Abstract

We have previously demonstrated that the in vivo vitreal injection of an antisense oligonucleotide directed to the kinesin heavy chain inhibits retinal kinesin synthesis by 82% and concomitantly inhibits rapid transport of total protein into the optic nerve by 70%. These results establish a major role for kinesin in rapid axonal transport in vivo. Recently, the cloning of a family of kinesin‐like molecules from the mammalian brain has been reported, and some of these proteins are also expressed in neurons. To assign a specific function to the kinesin heavy chain we inhibited the kinesin synthesis with an antisense kinesin oligonucleotide and assessed the axonal transport into the optic nerve of representative proteins from each of three vesicle classes that contain rapidly transported proteins. Marker proteins used were substance P for peptide‐containing synaptic vesicles, the amyloid precursor protein for plasma membrane precursor vesicles, and several integral synaptic vesicle proteins. Our results indicate that the major anterograde motor protein for all three vesicle classes utilizes kinesin heavy chain, although we discuss alternative explanations.

The axonal transport of mitochondria

“…There is abundant evidence, direct and indirect, that plus-enddirected kinesins provide force for anterograde axonal transport (Brady et al, 1990;Saxton et al, 1991;Gho et al, 1992;Amaratunga et al, 1993;Amaratunga et al, 1995;Hurd and Saxton, 1996;Stenoien and Brady, 1997;Gindhart et al, 1998;Martin et al, 1999b;Pilling, 2005). However, the diversity of kinesins in the nervous system presents many choices (Martin et al, 1999b;Hirokawa and Takemura, 2004;Hirokawa and Takemura, 2005;Lawrence et al, 2004).…”

Is Abnormal Axonal Transport a Cause, a Contributing Factor or a Consequence of the Neuronal Pathology in Alzheimer‘s Disease?

“…Numerous studies implicate kinesin-1 in the transport of APP into axons [43–47]. However, the notion that APP could have the function of recruiting kinesin-1 to cargo vesicles, as proposed by the Goldstein laboratory, confers to APP a major role in regulating the axonal transport.…”

Molecular motor function in axonal transport in vivo probed by genetic and computational analysis inDrosophila

“…The axonal transport of APP is of significant interest, owing to its likely involvement in the development of Alzheimer's disease, known vesicular properties, and fast axonal transport (Kamal et al ., 2000, 2001; Stokin et al ., 2005; Stokin and Goldstein, 2006; Duncan and Goldstein, 2006). Our focus on kinesin-1, as opposed to other members of the kinesin superfamily, is based on previous work showing that APP transport is abolished in the absence of kinesin-1 (Ferreira et al ., 1992; Amaratunga et al ., 1995; Yamazaki et al ., 1995; Kaether et al ., 2000) and that APP can associate with kinesin-1 either directly via interactions with the C-terminus domain of the light chain of kinesin-1 (Kamal et al ., 2000; Gunawardena and Goldstein, 2001) or indirectly through cytosolic adaptor proteins, such as the JNK-interacting protein 1 (Inomata et al ., 2003; Matsuda et al ., 2003). Combined with statistical analyses of the distribution of motion parameters, the experimental approach described here allowed us to test different models of motor interaction in vivo.…”