Polymorphic Strain Variation in Misfolded Proteins and Their Consequences in Neurodegenerative Diseases

A defining feature of most age-related neurodegenerative diseases is the misfolding, aggregation, and prion-like propagation of specific proteins, including amyloid-β, tau, α-synuclein, TDP-43, and the prion protein. A growing body of evidence demonstrates that these proteins do not adopt a single pathological conformation; rather, they exist as distinct structural variants, or strains, with unique biochemical properties, seeding capacities, cellular tropisms, and patterns of spread. This polymorphic strain variation helps explain the striking clinical and neuropathological heterogeneity observed within disorders such as Alzheimer’s disease, Parkinson’s disease, frontotemporal dementia, and prion diseases, where different patients can present with markedly different progression rates, brain region involvement, and symptom profiles. Advances in cryo-EM, seed amplification assays, and animal modeling have made it increasingly possible to define and differentiate these strains, opening new avenues for understanding disease mechanisms, refining diagnosis, and tailoring therapeutic interventions.

This Research Topic aims to advance understanding of how polymorphic strain variation in misfolded proteins shapes the pathogenesis, progression, and clinical heterogeneity of neurodegenerative diseases. We seek studies that characterize the structural, biochemical, and biological properties of distinct strains of amyloid-β, tau, α-synuclein, TDP-43, prion protein, and related aggregating proteins, and that link these properties to differences in seeding, spreading, cellular toxicity, and regional vulnerability in the aging brain. Contributions leveraging cryo-EM, solid-state NMR, seed amplification and PMCA-based assays, advanced animal and cellular models, and patient-derived material are particularly welcome. We also encourage translational work exploring how strain identity influences clinical phenotype, progression rate, biomarker signatures, and response to therapy, with the broader goal of supporting strain-informed diagnostics, prognostication, and precision therapeutic strategies for neurodegenerative disorders of aging.

We invite contributions spanning preclinical, translational, and clinical research that address polymorphic strain variation in misfolded proteins and its consequences for neurodegenerative diseases. Topics of interest include, but are not limited to:
• Structural characterization of protein strains by cryo-EM, solid-state NMR, and related methods
• Biochemical and conformational diversity of amyloid-β, tau, α-synuclein, TDP-43, and prion strains
• Strain-specific seeding, propagation, and cell-to-cell spread mechanisms
• Cellular and regional tropism of distinct strains in the aging brain
• Strain contributions to clinical and neuropathological heterogeneity
• Seed amplification assays (RT-QuIC, PMCA) for strain detection and differentiation
• Animal and cellular models for studying strain biology
• Strain-based biomarkers for diagnosis, prognosis, and disease monitoring
• Strain-informed therapeutic strategies, including immunotherapies and small molecules
• Implications of strain variation for clinical trial design and precision medicine in neurodegeneration

We encourage a wide range of submissions, including original research, methods papers, brief research reports, data reports, systematic reviews, mini reviews and perspectives.

Article types and fees

This Research Topic accepts the following article types, unless otherwise specified in the Research Topic description:

• Brief Research Report
• Data Report
• Editorial
• FAIR² Data
• General Commentary
• Hypothesis and Theory
• Methods
• Mini Review
• Opinion
• ... View all formats

Articles that are accepted for publication by our external editors following rigorous peer review incur a publishing fee charged to Authors, institutions, or funders.

Article types

This Research Topic accepts the following article types, unless otherwise specified in the Research Topic description:

• Brief Research Report
• Data Report
• Editorial
• FAIR² Data
• General Commentary
• Hypothesis and Theory
• Methods
• Mini Review
• Opinion
• Original Research
• Perspective
• Review
• Study Protocol
• Systematic Review
• Technology and Code

Keywords: Protein misfolding strains, Prion-like propagation, Conformational polymorphism, Seed amplification assays, Neurodegenerative disease heterogeneity

Important note: All contributions to this Research Topic must be within the scope of the section and journal to which they are submitted, as defined in their mission statements. Frontiers reserves the right to guide an out-of-scope manuscript to a more suitable section or journal at any stage of peer review.