Prion-like propagation of protein aggregation and related therapeutic strategies - PubMed (original) (raw)

Review

Sarah K Kaufman et al. Neurotherapeutics. 2013 Jul.

Abstract

Many neurodegenerative diseases are characterized by the progressive accumulation of aggregated protein. Recent evidence suggests the prion-like propagation of protein misfolding underlies the spread of pathology observed in these diseases. This review traces our understanding of the mechanisms that underlie this phenomenon and discusses related therapeutic strategies that derive from it.

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Figures

Fig. 1

Fig. 1

Amplification of a protein aggregate by templated conformational change. A native protein (blue circle) adopts a pathological conformation that facilitates aggregation into b-sheet rich structures. These structures can contact additional native proteins (green circles), adding them on to the aggregate by converting them to a specific aggregate structure

Fig. 2

Fig. 2

Mechanisms of aggregate release and uptake. a) Mechanisms of aggregate release. Proteins that misfold and aggregate might be secreted via several mechanisms. Direct penetration and vesicle fusion release aggregates directly into the media, whereas multivesicular body secretion and direct budding produce aggregate-laden vesicles. Therapeutic interventions can target the production of aggregate-prone proteins through RNA interference and antisense oligonucleotides. Small molecules might stabilize the native protein structure or inhibit templated misfolding of the cognate monomer. MVB, multivesicular body. b) Mechanisms of aggregate uptake. Fibrils are endocytosed by vesicle fusion or fluid-phase endocytosis. Aggregate escape into the cytosol allows further seeding and aggregation of endogenously expressed protein. Antibody blockade of cell attachment or endocytosis of aggregates will prevent the spread of misfolded protein, and therapies that induce relevant degradation pathways may increase the clearance of aggregates from the cell

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