A role of cellular translation regulation associated with toxic Huntingtin protein

Joag, Hiranmay; Ghatpande, Vighnesh; Desai, Meghal; Sarkar, Maitheli; Raina, Anshu; Shinde, Mrunalini; Chitale, Ruta; Deo, Ankita; Bose, Tania; Majumdar, Amitabha

doi:10.1007/s00018-019-03392-y

Cited by 17 publications

(29 citation statements)

References 62 publications

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“…This could impede normal RNA translational regulation ending in memory deficits even before neurodegeneration may arise. The observations that aggregates of huntingtin with polyQ expansions trap Orb2 13 , the Drosophila CPEB homolog, and reduce translation has recently led to a similar proposal 76 .…”

Section: Discussionmentioning

confidence: 90%

Molecular Determinants of Liquid Demixing and Amyloidogenesis in Human CPEB3

Mingo

López-García

Hervás

et al. 2020

Preprint

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The cytoplasmic polyadenylation element-binding protein 3 (CPEB3), is an RNA-binding protein which in its soluble state is localized in membraneless neuronal RNA granules keeping target mRNAs in a repressed state. The stimulus-dependent aggregation of CPEB3 activates target mRNAs translation, a central event for the maintenance of long-term memory-related synaptic plasticity in mammals. To date, the molecular determinants that govern both connected events remain unclear. Here, to gain insight into these processes, the biophysical properties of the human CPEB3 (hCPEB3) are characterized. We found that hCPEB3 homotypic condensation is mainly driven by hydrophobic interactions and occurs under physiological conditions. Moreover, hCPEB3 biomolecular condensates are dynamic inside living cells, whose localization and stabilization are mediated by its RNA-recognition domains.In contrast, the hCPEB3 polar N-terminal region is crucial for hCPEB3 amyloid-like aggregation in vitro, which is disrupted by the polyglutamine binding peptide 1 (QBP1), Aβ42 seeds and Hsp70, highlighting the importance of the Q4RQ4 tract as well as the hydrophobic residues for hCPEB3 functional aggregation. Based on these findings, we postulate a model for hCPEB3's role in memory persistence that advances a rather sophisticated control for hCPEB3 condensate dissociation and amyloid-like formation to achieve its physiological function.hCPEB3's demixing and amyloidogenesis Highlights • hCPEB3 forms toxic intermediates that persist longer than in other functional amyloids.• RNA-recognition domains stabilize hCPEB3 granule formation and dynamics.• Different segments within hCPEB3 promote amyloidogenesis and liquid demixing.• hCPEB3 amyloid formation requires both hydrophobic and polyQ segments. Graphical AbstracthCPEB3's demixing and amyloidogenesis

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Section: Discussionmentioning

confidence: 90%

Molecular Determinants of Liquid Demixing and Amyloidogenesis in Human CPEB3

Mingo

López-García

Hervás

et al. 2020

Preprint

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“…For example, work in yeast shows that molecular chaperones ( 67 , 68 ) and protein degradation ( 69 ) are critical systems to combat polyQ aggregation. In Drosophila S2 cells expressing long 138Q, but not shorter polyQ alleles, protein synthesis is downregulated via the translation regulator Orb2 ( 70 ). Studies using N2a cells, as we used, examined production and aggregate formation of HTT alleles with 18Q, 64Q or 150Q.…”

Section: Discussionmentioning

confidence: 99%

Formation and persistence of polyglutamine aggregates in mistranslating cells

Lant

Kiri

Duennwald

et al. 2021

Nucleic Acids Research

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In neurodegenerative diseases, including pathologies with well-known causative alleles, genetic factors that modify severity or age of onset are not entirely understood. We recently documented the unexpected prevalence of transfer RNA (tRNA) mutants in the human population, including variants that cause amino acid mis-incorporation. We hypothesized that a mistranslating tRNA will exacerbate toxicity and modify the molecular pathology of Huntington's disease-causing alleles. We characterized a tRNA Pro mutant that mistranslates proline codons with alanine, and tRNA Ser mutants, including a tRNA Ser AGA G35A variant with a phenylalanine anticodon (tRNA Ser AAA ) found in ∼2% of the population. The tRNA Pro mutant caused synthetic toxicity with a deleterious huntingtin poly-glutamine (polyQ) allele in neuronal cells. The tRNA Ser AAA variant showed synthetic toxicity with proteasome inhibition but did not enhance toxicity of the huntingtin allele. Cells mistranslating phenylalanine or proline codons with serine had significantly reduced rates of protein synthesis. Mistranslating cells were slow but effective in forming insoluble polyQ aggregates, defective in protein and aggregate degradation, and resistant to the neuroprotective integrated stress response inhibitor (ISRIB). Our findings identify mistranslating tRNA variants as genetic factors that slow protein aggregation kinetics, inhibit aggregate clearance, and increase drug resistance in cellular models of neurodegenerative disease.

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“…Interestingly, in a genome-wide screen in yeast, expression of a mHTT fragment (Htt103Q) causes a dramatic reduction in expression of genes involved in rRNA metabolism and ribosome biogenesis [ 64 ]. Moreover, cells expressing HttQ138 show a decreased translation by the prion-like protein and translation regulator Orb2, sequestered by mHTT aggregates [ 65 ]. Recently, mHTT has been reported to suppress protein synthesis in the same HD cell model adopted here by a mechanism involving ribosome stalling [ 66 ].…”

Section: Discussionmentioning

confidence: 99%

Nucleolar stress controls mutant Huntington toxicity and monitors Huntington’s disease progression

et al. 2021

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Transcriptional and cellular-stress surveillance deficits are hallmarks of Huntington’s disease (HD), a fatal autosomal-dominant neurodegenerative disorder caused by a pathological expansion of CAG repeats in the Huntingtin (HTT) gene. The nucleolus, a dynamic nuclear biomolecular condensate and the site of ribosomal RNA (rRNA) transcription, is implicated in the cellular stress response and in protein quality control. While the exact pathomechanisms of HD are still unclear, the impact of nucleolar dysfunction on HD pathophysiology in vivo remains elusive. Here we identified aberrant maturation of rRNA and decreased translational rate in association with human mutant Huntingtin (mHTT) expression. The protein nucleophosmin 1 (NPM1), important for nucleolar integrity and rRNA maturation, loses its prominent nucleolar localization. Genetic disruption of nucleolar integrity in vulnerable striatal neurons of the R6/2 HD mouse model decreases the distribution of mHTT in a disperse state in the nucleus, exacerbating motor deficits. We confirmed NPM1 delocalization in the gradually progressing zQ175 knock-in HD mouse model: in the striatum at a presymptomatic stage and in the skeletal muscle at an early symptomatic stage. In Huntington’s patient skeletal muscle biopsies, we found a selective redistribution of NPM1, similar to that in the zQ175 model. Taken together, our study demonstrates that nucleolar integrity regulates the formation of mHTT inclusions in vivo, and identifies NPM1 as a novel, readily detectable peripheral histopathological marker of HD progression.

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A role of cellular translation regulation associated with toxic Huntingtin protein

Cited by 17 publications

References 62 publications

Molecular Determinants of Liquid Demixing and Amyloidogenesis in Human CPEB3

Molecular Determinants of Liquid Demixing and Amyloidogenesis in Human CPEB3

Formation and persistence of polyglutamine aggregates in mistranslating cells

Nucleolar stress controls mutant Huntington toxicity and monitors Huntington’s disease progression

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