Amorphous protein aggregates stimulate plasminogen activation, leading to release of cytotoxic fragments that are clients for extracellular chaperones [Molecular Bases of Disease]

The misfolding of proteins and their accumulation in extracellular tissue compartments as insoluble amyloid or amorphous protein aggregates is a hallmark feature of many debilitating protein deposition diseases such as Alzheimers disease, prion diseases and type II diabetes. The plasminogen activation system (PAS) is best known as an extracellular fibrinolytic system, but was previously reported to also be capable of degrading amyloid fibrils. Here we show that amorphous protein aggregates interact with tPA and plasminogen, via an exposed lysine dependent mechanism, to efficiently generate plasmin. The insoluble aggregate-bound plasmin is shielded from inhibition by α;2-antiplasmin and degrades amorphous protein aggregates to release smaller, soluble but relatively hydrophobic fragments of protein (plasmin-generated protein fragments, PGPFs) that are cytotoxic. In vitro, both endothelial and microglial cells bound and internalised PGPFs before trafficking them to lysosomes. Clusterin and α2-macroglobulin bound to PGPFs to significantly ameliorate their toxicity. On the basis of these findings we hypothesize that, as part of the in vivo extracellular proteostasis system, the PAS may work synergistically with extracellular chaperones to safely clear large and otherwise pathological protein aggregates from the body.

from # All Medicine by Alexandros G. Sfakianakis via Alexandros G.Sfakianakis on Inoreader http://ift.tt/2uor5UD
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