Most neurodegenerative diseases are characterized by the intracellular or extracellular aggregation of misfolded proteins such as amyloid-β and tau in Alzheimer disease, α-synuclein in Parkinson disease, and TAR DNA-binding protein 43 in amyotrophic lateral sclerosis. Accumulating evidence from both human studies and disease models indicates that intercellular transmission and the subsequent templated amplification of these misfolded proteins are involved in the onset and progression of various neurodegenerative diseases. The misfolded proteins that are transferred between cells are referred to as ‘pathological seeds’. Recent studies have made exciting progress in identifying the characteristics of different pathological seeds, particularly those isolated from diseased brains. Advances have also been made in our understanding of the molecular mechanisms that regulate the transmission process, and the influence of the host cell on the conformation and properties of pathological seeds. The aim of this Review is to summarize our current knowledge of the cell-to-cell transmission of pathological proteins and to identify key questions for future investigation.
Cell-to-cell transmission and the subsequent amplification of pathological proteins is emerging as a common mechanism for the progression of various neurodegenerative diseases.
Transmission within the CNS as well as from the peripheral nervous system to the CNS has been reported for multiple pathological proteins.
Multiple molecular mechanisms involved in the secretion, uptake and transport of pathological seeds have been identified.
Neurodegenerative disease-related pathological proteins are conformationally diverse.
Various factors can modulate the transmission process, including neuronal activity, glial cells, genetic risk factors and interactions with other pathological proteins.
Antibodies against pathological seeds, which are designed to block the transmission process, are currently in clinical trials.
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The authors thank the Michael J. Fox Foundation.
The authors declare no competing interests.
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- Recombinant proteins
Proteins that are artificially expressed in, and purified from, bacteria.
The anatomical joining of two individuals.
- Microfluidic chambers
Cell culture chambers that enable the isolation of the axonal or dendritic component from cell bodies.
Vesicles (0.1–1 µm in diameter) that are budded and released directly from the plasma membrane.
- Direct translocation
Pore-mediated translocation across the plasma membrane.
- Tunnelling nanotubes
Protrusions that extend from the plasma membrane and enable the communication of cell contents between two cells.
- Protein misfolding cyclic amplification
The amplification of misfolded protein by repeated incubation with corresponding monomers.
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Peng, C., Trojanowski, J.Q. & Lee, V.M. Protein transmission in neurodegenerative disease. Nat Rev Neurol 16, 199–212 (2020). https://doi.org/10.1038/s41582-020-0333-7