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;
PubMed.
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 poten/papers/jip1-regulates-directionality-app-axonal-transport-coordinating-kinesin-and-dynein-motorstial 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 (Fu et al., 2013).
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 (Fu et al., 2013). 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 (Muresan et al., 2005).
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 (Muresan et al., 2009), 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 (Villegas et al., 2014). 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 (Muresan et al., 2009). 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 (Villegas et al., 2014).
The phosphorylation of APP at Thr668 is highly relevant to AD, since preventing it appears to protect against neurodegeneration in animal models of AD (Mazzitelli et al., 2011; Oulès et al., 2012; .Sclip et al., 2011; Yoon et al., 2012). Earlier studies indicated that JIP-1 regulates the phosphorylation, and the amyloidogenic processing, of APP (Inomata et al., 2003; Taru et al., 2002; Taru et al., 2002). 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 (Muresan and Muresan, 2005) 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 (Scheinfield et al., 2003). 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.
References:
Fu MM, Holzbaur EL.
JIP1 regulates the directionality of APP axonal transport by coordinating kinesin and dynein motors.
J Cell Biol. 2013 Aug 5;202(3):495-508.
PubMed.
Muresan Z, Muresan V.
Coordinated transport of phosphorylated amyloid-beta precursor protein and c-Jun NH2-terminal kinase-interacting protein-1.
J Cell Biol. 2005 Nov 21;171(4):615-25.
PubMed.
Villegas C, Muresan V, Ladescu Muresan Z.
Dual-tagged amyloid-β precursor protein reveals distinct transport pathways of its N- and C-terminal fragments.
Hum Mol Genet. 2014 Mar 15;23(6):1631-43. Epub 2013 Nov 7
PubMed.
Vagnoni A, Perkinton MS, Gray EH, Francis PT, Noble W, Miller CC.
Calsyntenin-1 mediates axonal transport of the amyloid precursor protein and regulates Aβ production.
Hum Mol Genet. 2012 Jul 1;21(13):2845-54.
PubMed.
Muresan V, Varvel NH, Lamb BT, Muresan Z.
The cleavage products of amyloid-beta precursor protein are sorted to distinct carrier vesicles that are independently transported within neurites.
J Neurosci. 2009 Mar 18;29(11):3565-78.
PubMed.
Mazzitelli S, Xu P, Ferrer I, Davis RJ, Tournier C.
The loss of c-Jun N-terminal protein kinase activity prevents the amyloidogenic cleavage of amyloid precursor protein and the formation of amyloid plaques in vivo.
J Neurosci. 2011 Nov 23;31(47):16969-76.
PubMed.
Oulès B, Del Prete D, Greco B, Zhang X, Lauritzen I, Sevalle J, Moreno S, Paterlini-Bréchot P, Trebak M, Checler F, Benfenati F, Chami M.
Ryanodine receptor blockade reduces amyloid-β load and memory impairments in Tg2576 mouse model of Alzheimer disease.
J Neurosci. 2012 Aug 22;32(34):11820-34.
PubMed.
Sclip A, Antoniou X, Colombo A, Camici GG, Pozzi L, Cardinetti D, Feligioni M, Veglianese P, Bahlmann FH, Cervo L, Balducci C, Costa C, Tozzi A, Calabresi P, Forloni G, Borsello T.
c-Jun N-terminal kinase regulates soluble Aβ oligomers and cognitive impairment in AD mouse model.
J Biol Chem. 2011 Dec 23;286(51):43871-80.
PubMed.
Yoon SO, Park DJ, Ryu JC, Ozer HG, Tep C, Shin YJ, Lim TH, Pastorino L, Kunwar AJ, Walton JC, Nagahara AH, Lu KP, Nelson RJ, Tuszynski MH, Huang K.
JNK3 perpetuates metabolic stress induced by Aβ peptides.
Neuron. 2012 Sep 6;75(5):824-37.
PubMed.
Inomata H, Nakamura Y, Hayakawa A, Takata H, Suzuki T, Miyazawa K, Kitamura N.
A scaffold protein JIP-1b enhances amyloid precursor protein phosphorylation by JNK and its association with kinesin light chain 1.
J Biol Chem. 2003 Jun 20;278(25):22946-55.
PubMed.
Taru H, Iijima K, Hase M, Kirino Y, Yagi Y, Suzuki T.
Interaction of Alzheimer's beta -amyloid precursor family proteins with scaffold proteins of the JNK signaling cascade.
J Biol Chem. 2002 May 31;277(22):20070-8.
PubMed.
Taru H, Kirino Y, Suzuki T.
Differential roles of JIP scaffold proteins in the modulation of amyloid precursor protein metabolism.
J Biol Chem. 2002 Jul 26;277(30):27567-74.
PubMed.
Muresan Z, Muresan V.
c-Jun NH2-terminal kinase-interacting protein-3 facilitates phosphorylation and controls localization of amyloid-beta precursor protein.
J Neurosci. 2005 Apr 13;25(15):3741-51.
PubMed.
Scheinfeld MH, Ghersi E, Davies P, D'Adamio L.
Amyloid beta protein precursor is phosphorylated by JNK-1 independent of, yet facilitated by, JNK-interacting protein (JIP)-1.
J Biol Chem. 2003 Oct 24;278(43):42058-63.
PubMed.
Comments
Rutgers - New Jersey Medical School
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 poten/papers/jip1-regulates-directionality-app-axonal-transport-coordinating-kinesin-and-dynein-motorstial 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 (Fu et al., 2013).
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 (Fu et al., 2013). 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 (Muresan et al., 2005).
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 (Muresan et al., 2009), 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 (Villegas et al., 2014). 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 (Muresan et al., 2009). 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 (Villegas et al., 2014).
The phosphorylation of APP at Thr668 is highly relevant to AD, since preventing it appears to protect against neurodegeneration in animal models of AD (Mazzitelli et al., 2011; Oulès et al., 2012; .Sclip et al., 2011; Yoon et al., 2012). Earlier studies indicated that JIP-1 regulates the phosphorylation, and the amyloidogenic processing, of APP (Inomata et al., 2003; Taru et al., 2002; Taru et al., 2002). 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 (Muresan and Muresan, 2005) 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 (Scheinfield et al., 2003). 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.
References:
Fu MM, Holzbaur EL. JIP1 regulates the directionality of APP axonal transport by coordinating kinesin and dynein motors. J Cell Biol. 2013 Aug 5;202(3):495-508. PubMed.
Muresan Z, Muresan V. Coordinated transport of phosphorylated amyloid-beta precursor protein and c-Jun NH2-terminal kinase-interacting protein-1. J Cell Biol. 2005 Nov 21;171(4):615-25. PubMed.
Villegas C, Muresan V, Ladescu Muresan Z. Dual-tagged amyloid-β precursor protein reveals distinct transport pathways of its N- and C-terminal fragments. Hum Mol Genet. 2014 Mar 15;23(6):1631-43. Epub 2013 Nov 7 PubMed.
Vagnoni A, Perkinton MS, Gray EH, Francis PT, Noble W, Miller CC. Calsyntenin-1 mediates axonal transport of the amyloid precursor protein and regulates Aβ production. Hum Mol Genet. 2012 Jul 1;21(13):2845-54. PubMed.
Muresan V, Varvel NH, Lamb BT, Muresan Z. The cleavage products of amyloid-beta precursor protein are sorted to distinct carrier vesicles that are independently transported within neurites. J Neurosci. 2009 Mar 18;29(11):3565-78. PubMed.
Mazzitelli S, Xu P, Ferrer I, Davis RJ, Tournier C. The loss of c-Jun N-terminal protein kinase activity prevents the amyloidogenic cleavage of amyloid precursor protein and the formation of amyloid plaques in vivo. J Neurosci. 2011 Nov 23;31(47):16969-76. PubMed.
Oulès B, Del Prete D, Greco B, Zhang X, Lauritzen I, Sevalle J, Moreno S, Paterlini-Bréchot P, Trebak M, Checler F, Benfenati F, Chami M. Ryanodine receptor blockade reduces amyloid-β load and memory impairments in Tg2576 mouse model of Alzheimer disease. J Neurosci. 2012 Aug 22;32(34):11820-34. PubMed.
Sclip A, Antoniou X, Colombo A, Camici GG, Pozzi L, Cardinetti D, Feligioni M, Veglianese P, Bahlmann FH, Cervo L, Balducci C, Costa C, Tozzi A, Calabresi P, Forloni G, Borsello T. c-Jun N-terminal kinase regulates soluble Aβ oligomers and cognitive impairment in AD mouse model. J Biol Chem. 2011 Dec 23;286(51):43871-80. PubMed.
Yoon SO, Park DJ, Ryu JC, Ozer HG, Tep C, Shin YJ, Lim TH, Pastorino L, Kunwar AJ, Walton JC, Nagahara AH, Lu KP, Nelson RJ, Tuszynski MH, Huang K. JNK3 perpetuates metabolic stress induced by Aβ peptides. Neuron. 2012 Sep 6;75(5):824-37. PubMed.
Inomata H, Nakamura Y, Hayakawa A, Takata H, Suzuki T, Miyazawa K, Kitamura N. A scaffold protein JIP-1b enhances amyloid precursor protein phosphorylation by JNK and its association with kinesin light chain 1. J Biol Chem. 2003 Jun 20;278(25):22946-55. PubMed.
Taru H, Iijima K, Hase M, Kirino Y, Yagi Y, Suzuki T. Interaction of Alzheimer's beta -amyloid precursor family proteins with scaffold proteins of the JNK signaling cascade. J Biol Chem. 2002 May 31;277(22):20070-8. PubMed.
Taru H, Kirino Y, Suzuki T. Differential roles of JIP scaffold proteins in the modulation of amyloid precursor protein metabolism. J Biol Chem. 2002 Jul 26;277(30):27567-74. PubMed.
Muresan Z, Muresan V. c-Jun NH2-terminal kinase-interacting protein-3 facilitates phosphorylation and controls localization of amyloid-beta precursor protein. J Neurosci. 2005 Apr 13;25(15):3741-51. PubMed.
Scheinfeld MH, Ghersi E, Davies P, D'Adamio L. Amyloid beta protein precursor is phosphorylated by JNK-1 independent of, yet facilitated by, JNK-interacting protein (JIP)-1. J Biol Chem. 2003 Oct 24;278(43):42058-63. PubMed.
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