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Related Experiment Video

Updated: Dec 8, 2025

Fractionation for Resolution of Soluble and Insoluble Huntingtin Species

Fractionation for Resolution of Soluble and Insoluble Huntingtin Species

Published on: February 27, 2018

Subcellular Localization And Formation Of Huntingtin Aggregates Correlates With Symptom Onset And Progression In A

Christian Landles¹, Rebecca E Milton¹, Nadira Ali¹

¹Huntington's Disease Centre, Department of Neurodegenerative Disease and UK Dementia Research Institute at UCL, Queen Square Institute of Neurology, UCL, Queen Square, WC1N 3BG, UK.

Brain Communications

|September 21, 2020

Summary

This summary is machine-generated.

Huntington's disease pathogenesis involves CAG repeat expansion in the HTT gene. Different CAG repeat lengths in mouse models show distinct aggregation patterns and disease progression, highlighting the need for subcellular analysis.

Keywords:

Huntington’s disease huntingtin aggregation and seeding polyglutamine somatic CAG instability transcriptional dysregulation

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Last Updated: Dec 8, 2025

Fractionation for Resolution of Soluble and Insoluble Huntingtin Species

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Published on: December 10, 2021

Area of Science:

Genetics
Neuroscience
Molecular Biology

Background:

Huntington's disease (HD) stems from CAG repeat expansion in the HTT gene.
Somatic CAG expansion is crucial in HD pathogenesis, with varying thresholds across tissues.
Incomplete splicing of HTT generates a toxic exon 1 protein fragment, with longer repeats producing more of this fragment.

Purpose of the Study:

To investigate the molecular and behavioral impacts of different CAG repeat lengths in the HTT gene.
To compare the consequences of expressing exon 1 HTT with 90 CAGs versus approximately 200 CAGs in the R6/2 mouse model.
To elucidate the relationship between HTT aggregation, subcellular localization, and disease progression in HD.

Main Methods:

Utilized the R6/2 mouse model with distinct CAG repeat expansions (90 and ~200 CAGs).
Analyzed nuclear and cytoplasmic aggregation of the HTT protein.
Assessed transcriptional dysregulation and behavioral phenotypes.
Characterized aggregate properties, including detergent solubility and seeding potential.

Main Results:

Earlier nuclear aggregation and transcriptional dysregulation observed in R6/2(CAG)90 mice.
Rapid cytoplasmic aggregate accumulation and behavioral deficits correlated with disease progression in R6/2(CAG)200 mice.
Distinct aggregate properties were found between the two mouse models, with nuclear aggregates in R6/2(CAG)90 mice showing different characteristics than cytoplasmic inclusion bodies in R6/2(CAG)200 mice.

Conclusions:

The subcellular localization and properties of HTT aggregates differ based on CAG repeat length and influence disease progression.
Somatic CAG expansion contributes to HD pathogenesis through the generation of toxic HTT fragments.
Comprehensive subcellular analysis is essential for understanding the complex relationship between HTT aggregation and HD phenotypes.