Progressive alterations of striatal polysomal architecture in a mouse model of Huntington's disease

Neurons rely on a precise spatial and temporal control of protein synthesis due to their highly polarized morphology and their functional singularities. Consequently, alterations in protein translation have been widely related to the development and progression of various neurological and neurodegenerative disorders, including Huntington's disease. Here we explored the architecture of polysomes in their native brain context by performing 3D electron tomography of striatal tissue derived from a knock-in mouse model of the disease. Results showed a progressive remodelling towards a polysomal compacted architecture that parallels in time the emergence and progression of symptoms in the mouse model. The aberrant architecture is compatible with ribosome stalling phenomena and, in fact, we detected an increase in the expression of the stalling release factor eIF5A2. Polysomal sedimentation gradients showed significant excess in the accumulation of free 40S ribosomal subunits in heterozygous striatal samples. Overall the results indicate that changes in the architecture of the protein synthesis machinery might be at the basis of translational alterations associated to Huntington's disease and open new avenues for understanding disease progression.

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Global ribosome profiling reveals that mutant huntingtin stalls ribosomes and represses protein synthesis independent of fragile X mental retardation protein

10.1101/629667 ◽

2019 ◽

Cited By ~ 7

Author(s):

Mehdi Eshraghi ◽

Pabalu Karunadharma ◽

Juliana Blin ◽

Neelam Shahani ◽

Emiliano Ricci ◽

...

Keyword(s):

Protein Synthesis ◽

Mental Retardation ◽

Huntington's Disease ◽

Huntington’S Disease ◽

Fragile X ◽

Skill Learning ◽

Mutant Huntingtin ◽

Ribosome Stalling ◽

Fragile X Mental Retardation ◽

Mental Retardation Protein

AbstractThe regulators that stall ribosome translocation are poorly understood. We find that polyglutamine-expanded mutant Huntingtin (mHtt), the Huntington’s disease (HD) causing protein, promotes ribosome stalling and physiologically suppresses protein synthesis. A comprehensive, genome-wide analysis of ribosome footprint profiling (Ribo-Seq) revealed widespread ribosome stalling on mRNA transcripts and a shift in the distribution of ribosomes toward the 5’ end, with single-codon unique pauses on selected mRNAs in HD cells. In Ribo-Seq, we found fragile X mental retardation protein (FMRP), a known regulator of ribosome stalling, translationally upregulated and it co-immunoprecipitated with mHtt in HD cells and postmortem brain. Depletion of FMRP gene, Fmr1, however, did not affect the mHtt-mediated suppression of protein synthesis or ribosome stalling in HD cells. Consistent with this, heterozygous deletion of Fmr1 in Q175FDN-Het mouse model, Q175FDN-Het; Fmr1+/–, showed no discernable phenotype, but a subtle deficit in motor skill learning. On the other hand, depletion of mHtt, which binds directly to ribosomes in an RNase-sensitive manner, enhanced global protein synthesis, increased ribosome translocation and decreased stalling. This mechanistic knowledge advances our understanding of the inhibitory role of mHtt in ribosome translocation and may lead to novel target(s) identification and therapeutic approaches that modulate ribosome stalling in HD.One Sentence SummaryHuntington’s disease (HD) protein, mHtt, binds to ribosomes and affects their translocation and promotes stalling independent of the fragile X mental retardation protein.

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Faculty Opinions recommendation of Time course of choice reaction time deficits in the Hdh(Q92) knock-in mouse model of Huntington's disease in the operant serial implicit learning task (SILT).

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.1108415.564465 ◽

2008 ◽

Author(s):

Allan Tobin

Keyword(s):

Reaction Time ◽

Mouse Model ◽

Huntington's Disease ◽

Huntington’S Disease ◽

Implicit Learning ◽

Choice Reaction Time ◽

Time Course ◽

Learning Task

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Faculty Opinions recommendation of Wheel running from a juvenile age delays onset of specific motor deficits but does not alter protein aggregate density in a mouse model of Huntington's disease.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.1106030.562154 ◽

2008 ◽

Author(s):

Allan Tobin

Keyword(s):

Mouse Model ◽

Huntington's Disease ◽

Huntington’S Disease ◽

Wheel Running ◽

Motor Deficits ◽

Protein Aggregate ◽

Juvenile Age

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Faculty Opinions recommendation of Progressive alterations in the hypothalamic-pituitary-adrenal axis in the R6/2 transgenic mouse model of Huntington's disease.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.13937.471441 ◽

2006 ◽

Author(s):

Paolo Beck-Peccoz

Keyword(s):

Mouse Model ◽

Huntington's Disease ◽

Huntington’S Disease ◽

Transgenic Mouse ◽

Transgenic Mouse Model ◽

Hypothalamic Pituitary Adrenal Axis ◽

Hypothalamic Pituitary Adrenal ◽

Adrenal Axis ◽

Pituitary Adrenal Axis

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Faculty Opinions recommendation of Targeting of XJB-5-131 to mitochondria suppresses oxidative DNA damage and motor decline in a mouse model of Huntington's disease.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.717987469.793472459 ◽

2013 ◽

Author(s):

John Lazo

Keyword(s):

Dna Damage ◽

Mouse Model ◽

Huntington's Disease ◽

Huntington’S Disease ◽

Oxidative Dna Damage

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Neuroimaging, Urinary, and Plasma Biomarkers of Treatment Response in Huntington’s Disease: Preclinical Evidence with the p75NTR Ligand LM11A-31

Neurotherapeutics ◽

10.1007/s13311-021-01023-8 ◽

2021 ◽

Author(s):

Danielle A. Simmons ◽

Brian D. Mills ◽

Robert R. Butler III ◽

Jason Kuan ◽

Tyne L. M. McHugh ◽

...

Keyword(s):

Mouse Model ◽

Huntington's Disease ◽

Huntington’S Disease ◽

Treatment Response ◽

Diffusion Tensor ◽

Disease Onset ◽

Therapeutic Effects ◽

Plasma Cytokine ◽

Cytokine Levels ◽

Pharmacodynamic Biomarkers

AbstractHuntington’s disease (HD) is caused by an expansion of the CAG repeat in the huntingtin gene leading to preferential neurodegeneration of the striatum. Disease-modifying treatments are not yet available to HD patients and their development would be facilitated by translatable pharmacodynamic biomarkers. Multi-modal magnetic resonance imaging (MRI) and plasma cytokines have been suggested as disease onset/progression biomarkers, but their ability to detect treatment efficacy is understudied. This study used the R6/2 mouse model of HD to assess if structural neuroimaging and biofluid assays can detect treatment response using as a prototype the small molecule p75NTR ligand LM11A-31, shown previously to reduce HD phenotypes in these mice. LM11A-31 alleviated volume reductions in multiple brain regions, including striatum, of vehicle-treated R6/2 mice relative to wild-types (WTs), as assessed with in vivo MRI. LM11A-31 also normalized changes in diffusion tensor imaging (DTI) metrics and diminished increases in certain plasma cytokine levels, including tumor necrosis factor-alpha and interleukin-6, in R6/2 mice. Finally, R6/2-vehicle mice had increased urinary levels of the p75NTR extracellular domain (ecd), a cleavage product released with pro-apoptotic ligand binding that detects the progression of other neurodegenerative diseases; LM11A-31 reduced this increase. These results are the first to show that urinary p75NTR-ecd levels are elevated in an HD mouse model and can be used to detect therapeutic effects. These data also indicate that multi-modal MRI and plasma cytokine levels may be effective pharmacodynamic biomarkers and that using combinations of these markers would be a viable and powerful option for clinical trials.

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