Vagnoni A, Glennon EB, Perkinton MS, Gray EH, Noble W, Miller CC.
Loss of c-Jun N-terminal kinase-interacting protein-1 does not affect axonal transport of the amyloid precursor protein or Aβ production.
Hum Mol Genet. 2013 Jul 9;
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In this paper, Vagnoni et al. reassess the role of c-Jun N-terminal kinase (JNK)-interacting protein-1 (JIP-1) in the transport, phosphorylation, and amyloidogenic processing of Aβ precursor protein (APP). Specifically, they ask whether the axonal transport of APP is impeded in neurons lacking JIP-1. They also ask whether the loss of JIP-1 leads to changes in the phosphorylation and the amyloidogenic processing of APP. These are extremely important questions, in view of a potential role for JIP-1 in the pathogenic mechanism of Alzheimer's disease (AD), which certainly includes abnormal trafficking and metabolism of APP. The focus of this paper on JIP-1 is fully justified, since JIP-1 is a major scaffold protein assisting the JNK complex (which phosphorylates APP), and binding both APP and kinesin-1, the major motor for anterograde APP transport.
With regard to transport, the authors find that the absence of JIP-1 has no effect on the motile properties of exogenously expressed APP-EGFP in cultured rat neurons. Earlier studies, cited in the paper, generally supported a role of JIP-1 in the transport of APP, possibly mediating the recruitment of kinesin-1 to the APP-carrying vesicles. Also, in a very recent study with live imaging of fluorescent APP in dorsal root ganglia neurons, an experimental setting quite similar to that of Vagnoni et al., Fu and Holzbaur found that JIP-1 is required for proper, long-range, anterograde and retrograde APP motility, and that—in the absence of JIP-1—the transport of APP is severely perturbed .
Why is there such a difference between studies using similar experimental approaches to study the transport of APP? The differences in the type of neurons, or the animal species—rat versus mouse—used for experimentation are unlikely explanations. Our own published data  supports a role for JIP-1, but strictly for the transport of Thr668-phosphorylated APP (pAPP), which usually represents a minute fraction of the total APP. In this respect, our results are in agreement with the live imaging results of Vagnoni et al., showing JIP-1-independent transport of total APP, which largely consists of nonphosphorylated APP. We also note that, while the elegant studies of Fu and Holzbaur unequivocally show a role for JIP-1 in the transport of APP, they also show that APP does move even in the absence of JIP-1; it moves less efficiently, and with perturbed regulation of directionality, but it moves . Thus, it is fair to say that JIP-1 is a regulatory factor of APP transport, but is not generally required for the transport of APP. This would also explain why total, mostly nonphosphorylated APP still accumulates at the neurite terminals in the absence of JIP-1, as we showed earlier .
We would like to make some general comments that need to be taken into consideration by future studies of APP transport. First, it is likely that APP is transported by several, sometimes redundant pathways, which could use different motors (e.g., kinesin-3, in addition to kinesin-1), and different adaptors to recruit the motors to the transport vesicle . JIP-1 and calsyntenin-1, another kinesin-1 cargo linker implicated in the transport of APP , are some—but certainly not all—of these. Second, the exogenously expressed, C-terminally tagged, fluorescent APP is a poor substitute for endogenous APP, for several reasons: the large YFP (or EGFP) tag certainly interferes—at least to some extent—with the binding of functional proteins to the cytoplasmic domain of APP, including the putative binding of the molecular motors; this could modify the transport characteristics of APP . Also, these types of constructs do not allow live imaging to discern between full-length APP and C-terminal fragments of APP, which could be abundant in neurons . Finally, the level of expression of the tagged APP—even if only slightly above normal APP levels—could again influence the interaction between APP and its multiple binding partners, thus leading to changes in the biology of APP, including the proper sorting to the cargo vesicles, and the recruitment of the motors .
The phosphorylation of APP at Thr668 is highly relevant to AD, since preventing it appears to protect against neurodegeneration in animal models of AD [6-9]. Earlier studies indicated that JIP-1 regulates the phosphorylation, and the amyloidogenic processing, of APP [10-12]. By contrast, Vagnoni et al. report that reducing JIP-1 to undetectable levels does not influence the phosphorylation and processing of APP, or Aβ production. This result is in full agreement with our published study  showing that under normal conditions JIP-1 has no significant role in the phosphorylation of APP. We also note that, in earlier work, the D'Adamio lab found that APP is phosphorylated by JNK independent of, yet facilitated by, JIP-1 . Therefore, similar to its effect on the transport of APP, JIP-1 is not required for, but could under certain conditions regulate, the phosphorylation of APP by JNK.
Fu MM, Holzbaur EL.
JIP1 regulates the directionality of APP axonal transport by coordinating kinesin and dynein motors.
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