The role of macropinocytosis in the propagation of protein aggregation associated with neurodegenerative diseases

Abstract

With the onset of the rapidly aging population, the impact of age related neurodegenerative diseases is becoming a predominant health and economic concern. Neurodegenerative diseases such as Alzheimer's disease, Creutzfeldt-Jakob disease (CJD), Parkinson's disease, Huntington's disease, frontotemporal dementia (FTD), and amyotrophic lateral sclerosis (ALS) result from the loss of a specific subsets of neurons, which is closely associated with accumulation and deposition of specific protein aggregates. Protein aggregation, or fibril formation, is a well-studied phenomenon that occurs in a nucleation-dependent growth reaction. Recently, there has been a swell of literature implicating protein aggregation and its ability to propagate cell-to-cell in the rapid progression of these diseases. In order for protein aggregation to be kindled in recipient cells it is a requisite that aggregates must be able to be released from one cell and then taken up by others. In this article we will explore the relationship between protein aggregates, their propagation and the role of macropinocytosis in their uptake. We highlight the ability of neurons to undergo stimulated macropinocytosis and identify potential therapeutic targets.

Keywords: amyloid fibrils; endocytosis; macropinocytosis; propagation; protein aggregation.

Figure 1

Schematic representation of amyloid fibril formation. (A) Fibril formation can be characterized by a lag phase where nucleation events occur, following critical nucleation a growth/elongation phase is observed which can proceed via primary (monomer addition) or secondary (fragmentation/secondary nucleation) events (B). During the latter stages, mature fibrils are formed which often display strong ThT emission signals. (C) Addition of fibrils or other functional seeds to the start of the reaction allows elongation to proceed without the requirement for primary nucleation removing the lag phase.

Figure 2

Propagation of aggregation and a proposed mechanism for aggregate uptake via macropinocytosis. (A) Protein aggregates form in neurons (primary nucleation) and have the potential to further nucleate the aggregation of other proteins. These protein aggregates can transfer directly from cell-to-cell through synaptic transfer, or be actively released via secretion mechanisms (e.g., exosomes) or in their naked form, either actively released from live cells or non-specifically released from dying cells, to neighboring interconnecting neurons. The uptake of such aggregates nucleates aggregation in naïve cells. (B) Aggregates may interact with cell surface receptors (such as HSG) (1) and promote the clustering and activation of signaling receptors such as receptor tyrosine kinases. This may result in the activation of signaling pathways such as those regulated by PAK1 and PKC (2) and subsequent mobilization of actin and formation of ruffles/blebs (3). Upon macropinosome closure (4) the structure is internalized (5). Given the unstructured nature of the macropinosomes it is likely that rigid aggregate structures may cause rupture (6) and allow access of the aggregates to the cytosol where nucleation of aggregation can proceed (7).