Protein transmission in neurodegenerative disease

• Published in: Nature reviews. Neurology Vol. 16; no. 4; pp. 199 - 212
• Main Authors: Peng, Chao, Trojanowski, John Q., Lee, Virginia M.-Y.
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 01.04.2020; Nature Publishing Group
• Subjects: 631/45/470/2284; 692/699/375/365; alpha-Synuclein - metabolism; Alzheimer Disease - metabolism; Alzheimer Disease - pathology; Amyloid beta-Peptides - metabolism; Amyotrophic Lateral Sclerosis - metabolism; Amyotrophic Lateral Sclerosis - pathology; Axonal Transport; Biological transport; Brain - metabolism; Brain - pathology; Cell Communication; Cell interaction; Degeneration; DNA-Binding Proteins - metabolism; Endocytosis; Exosomes - metabolism; Genetic Predisposition to Disease; Health aspects; Humans; Huntingtin Protein - metabolism; Huntington Disease - metabolism; Huntington Disease - pathology; Medicine; Medicine & Public Health; Membrane Fusion; Nanotubes; Nervous system; Neurodegenerative Diseases - metabolism; Neurodegenerative Diseases - pathology; Neuroglia - metabolism; Neurological research; Neurology; Neurons - metabolism; Parkinson Disease - metabolism; Parkinson Disease - pathology; Parkinson's disease; Physiological aspects; Protein Aggregation, Pathological - metabolism; Protein Aggregation, Pathological - pathology; Protein metabolism; Protein Transport; Proteins; Review Article; tau Proteins - metabolism; United States
• ISSN: 1759-4758; 1759-4766; 1759-4766
• DOI: 10.1038/s41582-020-0333-7

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. In this Review, Peng et al. summarize the evidence for cell-to-cell transmission of pathological proteins in neurodegenerative diseases such as Alzheimer disease and Parkinson disease, and identify key questions for future investigation. Key points 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.