Molecular mechanisms of the co-deposition of multiple pathological proteins in neurodegenerative diseases.

Intracellular inclusions composed of abnormal protein aggregates are one of the neuropathological features of neurodegenerative diseases, and the formation of intracellular aggregates is believed to be associated with neurodegeneration leading to the onset of these diseases. In typical or pure cases, characteristic pathologies with one particular protein, such as tau, alpha-synuclein or trans-activation response DNA protein 43 (TDP-43), can be observed in brains of patients. On the other hand, multiple protein pathologies co-exist in many cases, raising the possibility that they may influence each other reciprocally in the pathogenesis and progression of the diseases. However, the molecular mechanisms through which these proteins interact with each other and through which they are co-deposited in brains of patients remain poorly understood. In this review, we focus on the mechanisms of deposition of multiple pathological proteins, such as tau, alpha-synuclein and/or TDP-43, and on co-deposition models of these proteins in vitro and in vivo intended to recapitulate the multiple pathologies found in diseased brains.