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.
Highlights
Neurodegenerative diseases are closely linked to the formation and deposition of protein aggregates, quite often fibrillar, that accumulate intracellularly, such as α-synuclein in Parkinson’s disease (PD), or extracellularly, such as the amyloid-beta (Aβ) peptide plaques associated with Alzheimer’s disease (AD) (Chiti and Dobson, 2006)
It may help provide an explanation for the apparent patterns of pathology in amyotrophic lateral sclerosis (ALS), PD, and AD
In order to facilitate the propagation of intracellular aggregation in neurodegenerative diseases, such as ALS, PD, AD, and Huntington’s diseases (HD), active aggregate nuclei or seeds must gain access to the cytosol of naïve cells
Summary
Neurodegenerative diseases are closely linked to the formation and deposition of protein aggregates, quite often fibrillar, that accumulate intracellularly, such as α-synuclein in Parkinson’s disease (PD), or extracellularly, such as the amyloid-beta (Aβ) peptide plaques associated with Alzheimer’s disease (AD) (Chiti and Dobson, 2006). The peptides and proteins that aggregate are seemingly unrelated in terms of primary or tertiary structure, the resulting deposits are remarkably similar, often sharing a rope-like fibrillar morphology, a common cross-β core structure, and the ability to bind specific dyes such as thioflavin T and Congo red (Dobson, 2003). One potential mechanism of toxicity is mediated through exposed hydrophobic residues found on protein aggregates that have been shown to interact with cell surface receptors and membranes (Stefani and Dobson, 2003; Bolognesi et al, 2010), leading to membrane disruption and inappropriate signaling cascades
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