Abstract
Previous studies on Parkinson’s disease mechanisms have shown dysregulated extracellular transport of α-synuclein and growth factors in the extracellular space. In the human brain these consist of perineuronal nets, interstitial matrices, and basement membranes, each composed of a set of collagens, non-collagenous glycoproteins, proteoglycans, and hyaluronan. The manner by which amyloidogenic proteins spread extracellularly, become seeded, oligomerize, and are taken up by cells, depends on intricate interactions with extracellular matrix molecules. We sought to assess the alterations to structure of glycosaminoglycans and proteins that occur in PD brain relative to controls of similar age. We found that PD differs markedly from normal brain in upregulation of extracellular matrix structural components including collagens, proteoglycans and glycosaminoglycan binding molecules. We also observed that levels of hemoglobin chains, possibly related to defects in iron metabolism, were enriched in PD brains. These findings shed important new light on disease processes that occur in association with PD.
Highlights
Previous studies on Parkinson’s disease mechanisms have shown dysregulated extracellular transport of α-synuclein and growth factors in the extracellular space
Brain extracellular matrix (ECM) is composed of perineuronal nets (PNNs), interstitial matrices, and basement membranes, each consisting of a network of glycoproteins, proteoglycans, hyaluronan and c ollagens[5]
The concern for human brain biospecimen studies is that post mortem intervals (PMIs), disease states and effects of medication may bias the conclusions reached
Summary
Previous studies on Parkinson’s disease mechanisms have shown dysregulated extracellular transport of α-synuclein and growth factors in the extracellular space. Brain extracellular matrix (ECM) is composed of perineuronal nets (PNNs), interstitial matrices, and basement membranes (blood brain barrier), each consisting of a network of glycoproteins, proteoglycans, hyaluronan and c ollagens[5]. Inflammation and disruption of the blood brain barrier can lead to infiltration of fibroblasts and trigger a fibrotic response in an attempt to restore normal function[8] Such fibrosis demolishes the structure of the ECM, and impedes healing by secreting inhibitory molecules and serves as a barrier to axons. These inflammatory reactions lead to local neural degeneration and activation of glial cells.
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