Protein transmission in neurodegenerative disease

Abstract

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.

Fig. 1 |. Mechanisms for the transmission of pathological proteins between cells.

Pathological proteins, or ‘seeds’, are released from donor neurons and enter the extracellular space either as naked protein or in vesicles such as exosomes. Naked protein might be taken up by recipient neurons through receptor-mediated endocytosis (a), direct penetration of the plasma membrane (b) or fluid-phase endocytosis (c). Seeds in vesicles could be internalized through the fusion of vesicles with the plasma membrane (d). Seeds could also be transferred from a donor neuron to a recipient neuron via tunnelling nanotubes that directly connect the two cells (e). The transmission process can be modulated by multiple factors, including the clearance of pathological proteins by glial cells, neuronal activity, genetic risk factors and interaction of the seeds with other pathological proteins. Potential therapeutic interventions include antibodies that target the pathological seeds or the transmission machinery. Adapted from REF., Springer Nature Limited.

Fig. 2 |. Generation of different pathological protein strains.

Different intracellular environments can result in different pathological protein strains and several potential mechanisms for this differentiation have been suggested. a | Different intracellular environments could affect the initial protein misfolding process. b | Different intracellular environments could affect the templated amplification process. c | If pathological seeds were a mixture of different conformations or strains, different intracellular environments could lead to the selection and amplification of a specific conformation from the mixture.