Abstract
Maintaining the homeostasis of proteins (proteostasis) by controlling their synthesis, folding and degradation is a central task of cells and tissues. The gradual decline of the capacity of the various proteostasis machineries, frequently in combination with their overload through mutated, aggregation-prone proteins, is increasingly recognized as an important catalyst of age-dependent pathologies in the brain, most prominently neurodegenerative disorders. A dysfunctional proteostasis might also contribute to neurovascular disease as indicated by the occurrence of excessive protein accumulation or massive extracellular matrix expansion within vessel walls in conditions such as cerebral small vessel disease (SVD), a major cause of ischemic stroke, and cerebral amyloid angiopathy. Recent advances in brain vessel isolation techniques and mass spectrometry methodology have facilitated the analysis of cerebrovascular proteomes and fueled efforts to determine the proteomic signatures associated with neurovascular disease. In several studies in humans and mice considerable differences between healthy and diseased vessel proteomes were observed, emphasizing the critical contribution of an impaired proteostasis to disease pathogenesis. These findings highlight the important role of a balanced proteostasis for cerebrovascular health.
Highlights
Proteome homeostasis or proteostasis refers to the maintenance of all proteins of an organism in a conformation, concentration, and location that is required for their correct function (Balch et al, 2008)
Putative substrates were shown to be processed by HTRA1 in an in vitro assay (Zellner et al, 2018). These findings indicated the presence of a HTRA1 loss-of-function signature in the CADASIL vessel proteome and provided an unexpected mechanistical link between CADASIL and HTRA1-related small vessel disease (SVD)
Proteomic studies on human cerebrovascular tissue have identified several extracellular proteins accumulating with unexpected consistency in CADASIL and cerebral amyloid angiopathy (CAA), two neurovascular conditions caused by protein misfolding and aggregation
Summary
A dysfunctional proteostasis might contribute to neurovascular disease as indicated by the occurrence of excessive protein accumulation or massive extracellular matrix expansion within vessel walls in conditions such as cerebral small vessel disease (SVD), a major cause of ischemic stroke, and cerebral amyloid angiopathy. In several studies in humans and mice considerable differences between healthy and diseased vessel proteomes were observed, emphasizing the critical contribution of an impaired proteostasis to disease pathogenesis. These findings highlight the important role of a balanced proteostasis for cerebrovascular health
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