Baleriola J, Walker CA, Jean YY, Crary JF, Troy CM, Nagy PL, Hengst U.
Axonally synthesized ATF4 transmits a neurodegenerative signal across brain regions.
Cell. 2014 Aug 28;158(5):1159-72.
PubMed.
This Cell paper by Baleriola and colleagues describes how oligomeric Aβ1-42 can trigger the rapid recruitment and local translation of a defined set of mRNAs, including that for transcription factor ATF4, and AD-related messages such as APP in axons. Their evidence for the posttranscriptional regulation of locally translated messages in axons dovetails nicely with recent studies in the fragile X field regarding the presynaptic location and function of FMRP (see Akins et al., 2009, and 2012). FMRP is an RNA-binding protein that is found in both pre- and postsynaptic compartments and functions in protein synthesis-dependent long-term plasticity (see Till et al., 2010) as well as activity-dependent axon pruning (Tessier and Broadie, 2008). FMRP represses the translation of numerous synaptic mRNAs, including APP mRNA (see Westmark and Malter, 2007). APP is cleaved by β- and γ-secretases to generate Aβ, which has been proposed to act as a positive regulator of synaptic transmission presynaptically and a negative regulator postsynaptically (Palop and Mucke, 2010). The authors’ novel findings regarding axonal translation of APP suggest that both dendritic and axonal components of the synapse are important in maintaining homeostatic levels of APP and Aβ and contribute to a growing body of evidence supporting an Aβ-mediated feedback mechanism that regulates the synthesis of APP, likely through an FMRP- and mGluR5-dependent pathway.
References:
Akins MR, Berk-Rauch HE, Fallon JR.
Presynaptic translation: stepping out of the postsynaptic shadow.
Front Neural Circuits. 2009;3:17. Epub 2009 Nov 4
PubMed.
Akins MR, Leblanc HF, Stackpole EE, Chyung E, Fallon JR.
Systematic mapping of fragile X granules in the mouse brain reveals a potential role for presynaptic FMRP in sensorimotor functions.
J Comp Neurol. 2012 Nov 1;520(16):3687-706.
PubMed.
Till SM, Li HL, Miniaci MC, Kandel ER, Choi YB.
A presynaptic role for FMRP during protein synthesis-dependent long-term plasticity in Aplysia.
Learn Mem. 2011 Jan;18(1):39-48. Print 2011 Jan
PubMed.
Tessier CR, Broadie K.
Drosophila fragile X mental retardation protein developmentally regulates activity-dependent axon pruning.
Development. 2008 Apr;135(8):1547-57. Epub 2008 Mar 5
PubMed.
What is most striking in this work is the observation that Aβ initiates axonal synthesis, a process that has been discussed in other systems. Aβ induces the axonal synthesis of the transcription factor ATF4. The authors use a microfluidic chamber to isolate hippocampal axons from their cell bodies. As with many studies of AD-related molecular pathologic mechanistic findings, the initial studies are performed using embryonic hippocampal neurons, which do not replicate either the aged or diseased microneuronal environment.
Intriguingly, the authors were able to induce retrograde degeneration in select cholinergic neuronal basal forebrain subfields mainly within the nucleus of the diagonal band following Aβ-induced ATF4 transcriptional activity within hippocampal cholinergic projection axons. This degeneration could be blocked by co-injecting Atf4 siRNA into the mice. The selective effect of Aβ42 and ATF4 synthesis on cholinergic neurons of the diagonal band, and not the medial septum, in mice is fascinating. It is possible that not all cholinergic neurons respond to ATF4-induced neurodegenerative signaling, or, as hinted at by the authors, that ATF4 pathobiology may only induce a phenotypic downregulation of neurotransmitter expression in select cholinergic neuronal populations. This is possible but would be a bit surprising since both cholinergic subfields provide the major cholinergic innervation to the hippocampus.
It would have been interesting to know what division of the nucleus of the diagonal band the authors were referring to in their paper. One assumes it was the vertical limb of the diagonal band. The authors also report ATF4-containing axonal structures in the subiculum and the entorhinal cortex in human AD and control cases, with a higher frequency in the AD entorhinal cortex. This is interesting since they did not find ATF4 pathology in the hippocampus, which receives a major glutaminergic innervation pathway from the entorhinal cortex. It is this pathway that is disconnected early in AD. If ATF4 was a factor in retrograde induced degeneration, why did the authors not find ATF4 in the human hippocampus? In this regard, despite their control cases displaying moderate Braak pathology, they did not find ATF4 in these cases either. Perhaps the ATF4 retrograde neurodegenerative signaling pathway does not explain the mechanism underlying neuronal degeneration in human AD or plays a reduced role compared to that seen in mice.
Comments
University of Wisconsin
This Cell paper by Baleriola and colleagues describes how oligomeric Aβ1-42 can trigger the rapid recruitment and local translation of a defined set of mRNAs, including that for transcription factor ATF4, and AD-related messages such as APP in axons. Their evidence for the posttranscriptional regulation of locally translated messages in axons dovetails nicely with recent studies in the fragile X field regarding the presynaptic location and function of FMRP (see Akins et al., 2009, and 2012). FMRP is an RNA-binding protein that is found in both pre- and postsynaptic compartments and functions in protein synthesis-dependent long-term plasticity (see Till et al., 2010) as well as activity-dependent axon pruning (Tessier and Broadie, 2008). FMRP represses the translation of numerous synaptic mRNAs, including APP mRNA (see Westmark and Malter, 2007). APP is cleaved by β- and γ-secretases to generate Aβ, which has been proposed to act as a positive regulator of synaptic transmission presynaptically and a negative regulator postsynaptically (Palop and Mucke, 2010). The authors’ novel findings regarding axonal translation of APP suggest that both dendritic and axonal components of the synapse are important in maintaining homeostatic levels of APP and Aβ and contribute to a growing body of evidence supporting an Aβ-mediated feedback mechanism that regulates the synthesis of APP, likely through an FMRP- and mGluR5-dependent pathway.
References:
Akins MR, Berk-Rauch HE, Fallon JR. Presynaptic translation: stepping out of the postsynaptic shadow. Front Neural Circuits. 2009;3:17. Epub 2009 Nov 4 PubMed.
Akins MR, Leblanc HF, Stackpole EE, Chyung E, Fallon JR. Systematic mapping of fragile X granules in the mouse brain reveals a potential role for presynaptic FMRP in sensorimotor functions. J Comp Neurol. 2012 Nov 1;520(16):3687-706. PubMed.
Till SM, Li HL, Miniaci MC, Kandel ER, Choi YB. A presynaptic role for FMRP during protein synthesis-dependent long-term plasticity in Aplysia. Learn Mem. 2011 Jan;18(1):39-48. Print 2011 Jan PubMed.
Tessier CR, Broadie K. Drosophila fragile X mental retardation protein developmentally regulates activity-dependent axon pruning. Development. 2008 Apr;135(8):1547-57. Epub 2008 Mar 5 PubMed.
Westmark CJ, Malter JS. FMRP mediates mGluR5-dependent translation of amyloid precursor protein. PLoS Biol. 2007 Mar;5(3):e52. PubMed.
Palop JJ, Mucke L. Amyloid-beta-induced neuronal dysfunction in Alzheimer's disease: from synapses toward neural networks. Nat Neurosci. 2010 Jul;13(7):812-8. PubMed.
Barrow Neurological Institute
What is most striking in this work is the observation that Aβ initiates axonal synthesis, a process that has been discussed in other systems. Aβ induces the axonal synthesis of the transcription factor ATF4. The authors use a microfluidic chamber to isolate hippocampal axons from their cell bodies. As with many studies of AD-related molecular pathologic mechanistic findings, the initial studies are performed using embryonic hippocampal neurons, which do not replicate either the aged or diseased microneuronal environment.
Intriguingly, the authors were able to induce retrograde degeneration in select cholinergic neuronal basal forebrain subfields mainly within the nucleus of the diagonal band following Aβ-induced ATF4 transcriptional activity within hippocampal cholinergic projection axons. This degeneration could be blocked by co-injecting Atf4 siRNA into the mice. The selective effect of Aβ42 and ATF4 synthesis on cholinergic neurons of the diagonal band, and not the medial septum, in mice is fascinating. It is possible that not all cholinergic neurons respond to ATF4-induced neurodegenerative signaling, or, as hinted at by the authors, that ATF4 pathobiology may only induce a phenotypic downregulation of neurotransmitter expression in select cholinergic neuronal populations. This is possible but would be a bit surprising since both cholinergic subfields provide the major cholinergic innervation to the hippocampus.
It would have been interesting to know what division of the nucleus of the diagonal band the authors were referring to in their paper. One assumes it was the vertical limb of the diagonal band. The authors also report ATF4-containing axonal structures in the subiculum and the entorhinal cortex in human AD and control cases, with a higher frequency in the AD entorhinal cortex. This is interesting since they did not find ATF4 pathology in the hippocampus, which receives a major glutaminergic innervation pathway from the entorhinal cortex. It is this pathway that is disconnected early in AD. If ATF4 was a factor in retrograde induced degeneration, why did the authors not find ATF4 in the human hippocampus? In this regard, despite their control cases displaying moderate Braak pathology, they did not find ATF4 in these cases either. Perhaps the ATF4 retrograde neurodegenerative signaling pathway does not explain the mechanism underlying neuronal degeneration in human AD or plays a reduced role compared to that seen in mice.
Make a Comment
To make a comment you must login or register.