Protein-First, but Not Protein-Only: Rethinking Neurodegenerative Diseases Through Transgenic Mouse Models

Area of Science:

• Neuroscience
• Molecular Biology
• Genetics

Background:

• Neurodegenerative diseases pose a significant global health challenge.
• These disorders are mechanistically linked to protein misfolding, impaired proteostasis, and neuroinflammation.

Purpose of the Study:

• To discuss major neurodegenerative diseases through the lens of disease-associated proteins and experimental modeling.
• To advocate for a protein-centered framework for understanding disease mechanisms and selecting appropriate models.

Main Methods:

• Review of major neurodegenerative diseases including Alzheimer's, Parkinson's, ALS, and Huntington's disease.
• Analysis of transgenic and genetically engineered mouse models for studying pathogenic proteins like amyloid-β, tau, and α-synuclein.
• Integration of mouse models with human cellular models, postmortem tissue, omics, and biomarker validation.

Main Results:

• A protein-centered framework aids in understanding disease mechanisms and selecting models.
• Transgenic mouse models are essential but have limitations such as overexpression and familial bias.
• A portfolio of diverse models is more productive than seeking a single 'best' model.

Conclusions:

• A protein-centric view, combined with a portfolio of complementary models, enhances mechanistic insight into neurodegeneration.
• Integrating various model systems strengthens translational relevance and predictive value in preclinical research.
• Addressing limitations of current models is key to advancing neurodegenerative disease research.