Models in Huntington's Disease Research

Huntington's Disease (HD) is an autosomal dominant neurodegenerative disorder triggered by abnormal amplification of CAG trinucleotide repeats in the HTT gene. The core pathological mechanism is the neurotoxicity of mutant Huntington's protein (mHTT), which leads to selective degeneration of basal ganglia and cortical neurons, with clinical manifestations of choreiform movements, cognitive decline, and psychiatric disorders. Due to ethical and technical constraints in human research, animal and cellular models have become key tools for unraveling disease mechanisms and developing therapies.

Here, Creative Biolabs, as a global leading biotechnology service platform, focuses on providing customized solutions for HD research, covering the complete chain from basic mechanism exploration to preclinical drug development. Its core strength lies in integrating cutting-edge technology platforms and disease-specific models to help researchers and pharmaceutical companies accelerate HD research.

Table 1. Different models in HD research

Genetic and Clinical Features of Huntington's Disease

HD Genetic Basis

Huntington's disease is caused by CAG repeat expansion in the HTT gene, with normal repeats ranging from 6 to 34 and pathogenic repeats ≥36. The number of repeats inversely correlates with age of onset and tends to expand more in paternal inheritance. This expansion leads to abnormal polyglutamine (polyQ) structures in the HTT protein, causing misfolding, aggregation, and neuronal damage through RNA toxicity and mitochondrial dysfunction.

Figure 1. Illustration of CAG Amplification.

HD Clinical Characteristics

Early symptoms include choreiform involuntary movements, progressing to rigidity and slowed movement. Cognitive decline and psychiatric issues like depression and anxiety are common, while adolescent-onset cases show rapid dystonia progression. Imaging typically reveals basal ganglia glucose metabolism reduction and caudate nucleus atrophy, key pathological features of the disease.

Animal Models in Huntington's Disease Research

Transgenic Mouse Models

Table 2. Typical Transgenic Mouse Models

Strengths and limitations: high genetic correlation, but high phenotypic heterogeneity (e.g., lifespan differences) and inability to fully mimic selective neuronal loss in humans.

Knock-in Mouse Models

• Principle: CAG repeats are inserted into the endogenous mouse HTT gene through homologous recombination, preserving the wild-type allele and mimicking the heterozygous genetic state.
• Representative models: zQ175 and HdhQ150, showing delayed dyskinesia and intranuclear inclusion bodies, suitable for studying early molecular events.
• Advantages: gene expression is more precise, avoiding non-specific effects caused by transgene overexpression; limitation is slow phenotypic progression, requiring long-term observation.

Figure 2. HTTexon1 protein drives early aggregation in zQ175 knock-in mice.^1,2

Drosophila Models

• Molecular mechanism: Drosophila expressing mHTT fragment (e.g. HTT93Q) reveals the defective function of mitochondrial respiratory chain complex, and the phenotype can be rescued by expressing alternative enzymes (e.g. Ndi1, AOX).
• Drug screening: NUB1 protein improves motor function by promoting mHTT ubiquitination degradation, providing an efficient platform for intervention target validation.
• Advantages: short life cycle (~2 weeks), abundant genetic tools, but lacks the complexity of the mammalian nervous system.

Large Animal Models

• Pig models: using gene editing technology to knock-in 150 CAG repeats to reproduce selective degeneration of the striatum and motor deficits for the first time in large animals, suitable for drug metabolism and brain-targeted therapy evaluation.
• Non-human primates: brain structure is highly similar to humans, but high cost, ethical controversy, and limited application at present.
• Value: bridging the translational gap between mice and humans, especially indispensable in preclinical validation of gene therapies (e.g. AAV vector delivery).

Cell Models in Huntington's Disease research

Immortalized Cell Lines

Neuroblastoma: easily transfected with mHTT for the study of protein aggregation and apoptotic pathways, but the tumor origin leads to an aberrant state of differentiation, limiting physiological relevance.

Primary Neuronal Culture

• Applications: neurons from HD mice or patient brain tissue can be directly observed for synaptic transmission abnormalities and calcium homeostasis dysregulation, used for high throughput drug screening.
• Technical challenges: need to avoid glial cell proliferation interference and optimize the automated dispensing system to improve throughput.

iPSC-Derived Models

• Technical breakthrough: Patient-derived iPSC differentiates into medium-sized multi-spiny neurons (MSN), recapitulating the transcriptional dysregulation and mitochondrial damage associated with CAG repeat expansion.
• Difficulties: Insufficient cell maturity, requires 3D culture or organoid technology to enhance functionality.
• Clinical translation: Combining gene editing correction of mutant alleles provides a platform for personalized drug testing.

Applications and Future Directions in HD Research

Mechanism and Therapy Development

• Gene editing therapies: knockdown of mutant alleles significantly improved motor symptoms and neuropathology in HD pig models, validating the feasibility of targeting HTT.
• Small molecule drugs: histone deacetylase inhibitors based on Drosophila screening delayed neuronal degeneration and entered clinical trials.

Biomarker Discovery

Cross-species validation: identification of conserved biomarkers by integrating mouse, pig, and human data through databases.

Why Creative Biolabs?

Creative Biolabs specializes in providing full-process solutions for HD research, covering model development, drug screening and translational medicine research relying on the following core services:

• Huntington's Disease Modeling Service
• Immortalized Cell Line Preparation Service
• High-Throughput Phenotypic Screening Service
• STEMOD™ Advanced Drug Discovery Service

Contact us today to kickstart your HD research acceleration program and make meaningful strides toward novel therapeutic breakthroughs.

References

1. Smith, Edward J., et al. "Early Detection of Exon 1 Huntingtin Aggregation in zQ175 Brains by Molecular and Histological Approaches." Brain Communications, vol. 5, no. 1, Dec. 2022, p. fcad010. https://doi.org/10.1093/braincomms/fcad010.
2. Distributed under Open Access license CC BY 4.0, without modification.

For Research Use Only. Not For Clinical Use.