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www.biorxiv.org www.biorxiv.org
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Review coordinated by Life Science Editors Foundation
Reviewed by: Dr. Angela Andersen, Life Science Editors Foundation & Life Science Editors. *Assisted by NotebookLM.
Potential Conflicts of Interest: None
Under review at Nature Portfolio
Punchline: Neurons under stress can locally synthesize Heat Shock Proteins (HSPs) in dendrites by increasing the transport of their mRNAs from the soma.
Why is this interesting? This is a previously unknown mechanism for locally synthesizing HSPs in neuronal dendrites in response to stress. It could shed light on therapeutic strategies for neurodegenerative diseases, which are characterized by a loss of proteostasis.
Background:
- • Maintaining proteostasis is difficult for neurons because of their complex polarized morphology and the need for constant remodeling of the synaptic proteome.
- • Local Translation in Neurons: The concept of local translation, particularly within neuronal dendrites, was already well-established. mRNA localization and local translation are fundamental processes in neurons, allowing for spatial and temporal control of protein synthesis. This is particularly crucial in dendrites, which are distant from the soma and require localized protein synthesis for synaptic plasticity and other functions.
- • HSPs and Proteostasis: The importance of heat shock proteins (HSPs) in maintaining cellular proteostasis was also well-understood. HSPs act as chaperones, assisting in the proper folding of proteins and preventing the formation of harmful aggregates.
- • RNA-Binding Proteins and mRNA Localization: RNA-binding proteins (RBPs) play a critical role in regulating mRNA localization and translation. These proteins often recognize mRNAs and direct their transport to specific subcellular locations.
Results: * • When hippocampal and spinal cord motor neurons are stressed, they increase the transport of HSP mRNAs to the dendrites. * • Used a variety of techniques to stress the neurons, including inhibiting the proteasome, hypoxia, and exposure to amyloid-beta peptides. * • All of these stresses led to an increase in the levels of HSP mRNAs in the dendrites. * • The increase in HSP mRNA levels in the dendrites was accompanied by an increase in the levels of HSP proteins in the dendrites. * • This suggests that the HSP mRNAs are being translated into proteins in the dendrites. * • Transport of HSP mRNAs to the dendrites was dependent on the microtubule motor protein dynein. * • Two RNA-binding proteins, FUS and HNRNPA2B1, regulate the transport of HSP mRNAs to dendrites. * • Depletion of FUS or expression of the ALS-associated HNRNPA2B1 D290V mutation impaired the dendritic localization of HSP mRNAs in mouse and human motor neurons.
Discussion: * • Stress-Responsive HSP mRNA Transport and Translation in Dendrites: While previous studies had identified local translation of some proteins in dendrites and recognized the role of HSPs in neurons, this paper specifically focuses on the regulated transport and localized translation of HSP mRNAs in dendrites as a key mechanism for responding to proteotoxic stress. This adds a new layer of understanding to neuronal stress responses. * • Identification of FUS and HNRNPA2B1 as Key Regulators: The study goes a step further by identifying and characterizing the specific roles of RNA-binding proteins FUS and HNRNPA2B1 in regulating HSP mRNA transport. This mechanistic insight into how HSP mRNA localization is controlled enhances our understanding of how neurons fine-tune proteostasis in a spatially defined manner. * • Linking HSP mRNA Localization to ALS: The study makes a significant connection between the dysregulation of HSP mRNA localization and amyotrophic lateral sclerosis (ALS). By demonstrating that an ALS-associated mutation in HNRNPA2B1 (D290V) impairs HSPA8 mRNA localization and increases neuronal vulnerability, the study provides a potential molecular mechanism for this devastating neurodegenerative disease. This link between impaired local translation, proteostasis, and ALS opens up new avenues for research and potential therapeutic interventions.
Limitations: • Experiments conducted in cultured neurons.
Future work: * • Investigate the role of this mechanism in vivo. * • Determine whether this mechanism is impaired in other neurodegenerative diseases. * • Inform therapeutic strategies that can target this mechanism to treat or prevent neurodegenerative diseases.
Selected Reading 1. Bourke, Ashley M. et al. De-centralizing the Central Dogma: mRNA translation in space and time Molecular Cell, Volume 83, Issue 3, 452 – 468 (2023) 2. Davidson, Alexander et al. Localized Translation of gurken/TGF-α mRNA during Axis Specification Is Controlled by Access to Orb/CPEB on Processing Bodies Cell Reports, Volume 14, Issue 10, 2451 – 2462 (2016) 3. Gehrke, Stephan et al. PINK1 and Parkin Control Localized Translation of Respiratory Chain Component mRNAs on Mitochondria Outer Membrane Cell Metabolism, Volume 21, Issue 1, 95 – 108 (2015) 4. Hacisuleyman, E., Hale, C.R., Noble, N. et al. Neuronal activity rapidly reprograms dendritic translation via eIF4G2:uORF binding. Nat Neurosci 27, 822–835 (2024). 5. Höpfler, Markus et al. Control of mRNA fate by its encoded nascent polypeptide Molecular Cell, Volume 83, Issue 16, 2840 – 2855 (2023) 6. Park, Sungjin et al. The mammalian midbody and midbody remnant are assembly sites for RNA and localized translation Developmental Cell, Volume 58, Issue 19, 1917 - 1932.e6 (2023) 7. Lautier, Ophélie et al. Co-translational assembly and localized translation of nucleoporins in nuclear pore complex biogenesis Molecular Cell, Volume 81, Issue 11, 2417 - 2427.e5 (2021) 8. Ramat, A., Haidar, A., Garret, C. et al. Spatial organization of translation and translational repression in two phases of germ granules. Nat Commun 15, 8020 (2024).
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- Oct 2023
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docdrop.org docdrop.org
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the great Oliver Sacks once said a neuron is a neuron more or less regardless of species neurons do largely similar sorts 00:10:34 of things regardless of what animal you may find them in f
- for: example, example - evolutionary convergence, evolutionary convergence - neuron. Oliver Sachs
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- Dec 2021
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www.nature.com www.nature.com
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To test whether these distributed representations of meaning are neurally plausible, a number of studies have attempted to learn a mapping between particular semantic dimensions and patterns of brain activation
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URL
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cloud.google.com cloud.google.com
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the only thing an artificial neuron can do: classify a data point into one of two kinds by examining input values with weights and bias.
How does this relate to "weighted sum shows similarity between the weights and the inputs"?
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- Jul 2021
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mlech26l.github.io mlech26l.github.io
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In our research, i.e., the wormnet project, we try to build machine learning models motivated by the C. elegans nervous system. By doing so, we have to pay a cost, as we constrain ourselves to such models in contrast to standard artificial neural networks, whose modeling space is purely constraint by memory and compute limitations. However, there are potentially some advantages and benefits we gain. Our objective is to better understand what’s necessary for effective neural information processing to emerge.
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- Jun 2021
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cloud.google.com cloud.google.com
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"dividing n-dimensional space with a hyperplane."
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- Mar 2021
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iu.mediaspace.kaltura.com iu.mediaspace.kaltura.com
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MultiNet Webinar Series: Manlio De Domenico—Indiana University. (n.d.). Retrieved 1 March 2021, from https://iu.mediaspace.kaltura.com/media/MultiNet+Webinar+SeriesA+Manlio+De+Domenico/1_242n97rr
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- Jan 2019
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pegasus.cc.ucf.edu pegasus.cc.ucf.eduChapter3.pdf11
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reticular theory.
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gap junttion
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Electrical synapses
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synaptic cleft
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chemical synapse,
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Dendrites receive incoming signals and carry them to the cell body
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Axons carry signals (action potentials) away from the cell body and toward the synapse
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A synapse is a junction between two neurons, that is, between the axon terminal of the presynaptic cell and the dendrite (or sometimes, the cell body itself) of the postsynaptic cell.
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Basic Neuron Anatomy
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Neurons, or nerve cells, consist of three major parts: cell body (soma), axon, and dendrites.
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the neuron doctrine
related articles:
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- Feb 2018
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www.sciencenews.org www.sciencenews.org
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Cilia in the brain may be busier than previously thought
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