["Protein cancers" hypothesis for neurodegenerative diseases]

Area of Science:

• Neurobiology
• Molecular Biology
• Biochemistry

Context:

• Intracellular filamentous inclusions of amyloid-like proteins are hallmarks of neurodegenerative disorders.
• The spread of these pathological proteins and its mechanisms remain poorly understood.
• Abnormal protein aggregation correlates with disease progression, but propagation pathways are unclear.

Purpose:

• To investigate the molecular mechanisms of pathological protein spread in neurodegenerative diseases.
• To demonstrate seed-dependent polymerization and cell death using a novel in-cell seeding method.
• To explore the cell-to-cell propagation hypothesis for amyloid-like protein pathologies.

Summary:

• A novel method introduced amyloid seeds into cells, inducing seed-dependent polymerization of alpha-synuclein and tau proteins into filamentous deposits.
• Overexpression alone did not cause inclusions, but introduced fibril seeds triggered abundant alpha-synuclein inclusions and cell death.
• Similar results were observed with tau isoforms, supporting the hypothesis that amyloid-like proteins propagate from cell to cell.

Impact:

• Provides experimental evidence for cell-to-cell propagation of pathological proteins like alpha-synuclein and tau.
• Suggests that neurodegenerative diseases driven by amyloid-like proteins could be viewed as 'protein cancers' due to their metastatic-like spread.
• Highlights the potential for therapeutic strategies targeting protein propagation in neurodegenerative conditions.