Localized molecular chaperone synthesis maintains neuronal dendrite proteostasis

  1. Célia Alecki
  2. Javeria Rizwan
  3. Phuong Le
  4. Suleima Jacob-Tomas
  5. Mario Fernandez-Comaduran
  6. Morgane Verbrugghe
  7. Jia Ming Stella Xu
  8. Sandra Minotti
  9. James Lynch
  10. Jeetayu Biswas
  11. Tad Wu
  12. Heather Durham
  13. Gene W. Yeo
  14. Maria Vera

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Abstract

Proteostasis is maintained through regulated protein synthesis and degradation and chaperone-assisted protein folding. However, this is challenging in neuronal projections because of their polarized morphology and constant synaptic proteome remodeling. Using high-resolution fluorescence microscopy, we discovered that hippocampal and spinal cord motor neurons of mouse and human origin localize a subset of chaperone mRNAs to their dendrites and use microtubule-based transport to increase this asymmetric localization following proteotoxic stress. The most abundant dendritic chaperone mRNA encodes a constitutive heat shock protein 70 family member (HSPA8). Proteotoxic stress also enhanced HSPA8 mRNA translation efficiency in dendrites. Stress-mediated HSPA8 mRNA localization to the dendrites was impaired by depleting fused in sarcoma—an amyotrophic lateral sclerosis-related protein—in cultured spinal cord mouse motor neurons or by expressing a pathogenic variant of heterogenous nuclear ribonucleoprotein A2/B1 in neurons derived from human induced pluripotent stem cells. These results reveal a crucial and unexpected neuronal stress response in which RNA-binding proteins increase the dendritic localization of HSPA8 mRNA to maintain proteostasis and prevent neurodegeneration.

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  1. Life Science Editors Foundation

    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).
  2. Version published to 10.1101/2023.10.03.560761v2 on bioRxiv
  3. Version published to 10.1101/2023.10.03.560761v1 on bioRxiv