Cellular mechanisms of protein aggregate propagation

Abstract

Purpose of review: New research on the mechanisms of neurodegeneration highlights parallels between prion disease pathogenesis and other, more common disorders not typically thought to be infectious. This involves propagation of protein misfolding from cell to cell by templated conformational change. This review focuses on the cell biology that underlies propagation of protein aggregation between cells, including a discussion of protein biochemistry and relevant mouse models.

Recent findings: Like the prion protein, several other proteins exhibit self-propagating fibrillar conformations in vitro. Multiple cellular studies have now implicated endocytic mechanisms in the uptake of aggregates into cells. Aggregates that enter cells somehow escape endocytic vesicles to contact cytosolic protein. The mechanism of release of protein monomers and aggregates from cells is not well understood. Animal models have confirmed that brain lysates and purified protein can accelerate brain pathology in a manner similar to prions.

Summary: Aggregate flux in and out of cells likely contributes to the progression of neuropathology in neurodegenerative diseases. A better understanding of these mechanisms is emerging and can help explain local spread of protein aggregation and the role of neural networks in disease. This will also inform new therapeutic strategies aimed at blocking this process.

FIGURE 1

Transcellular propagation of protein misfolding. A: Extracellular aggregates are internalized into cells via unconventional endocytosis (i.e., macropinocytosis). B: Endocytosed aggregates escape the vesicular lumen to reach the cytosol and seed aggregation of cognate monomer. C: Newly formed endogenous aggregates are associated with aggresomes. D: Endogenous aggregates are released by the cell into the extracellular space via an unknown mechanism. E: A neighboring cell internalizes the released aggregate and reinitiates the cycle.