The proteostasis network provides targets for neurodegeneration

Abstract

The production, quality control, and degradation of proteins are a tightly controlled process necessary for cell health. In order to regulate this process, cells rely upon a network of molecular chaperone proteins that bind misfolded proteins and help them fold correctly. In addition, some molecular chaperones can target terminally misfolded proteins for degradation. Neurons are particularly dependent upon this “proteostasis” system, failures in which lead to neurodegenerative disease. In this review, we identify opportunities for modulating molecular chaperone activity with small molecules, which could lower the burden of misfolded protein within neurons, reducing cell death and ameliorating the effects of neurodegeneration. Linked Articles This article is part of a themed section on Therapeutics for Dementia and Alzheimer's Disease: New Directions for Precision Medicine. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v176.18/issuetoc

The Down-Regulation of Clusterin Expression Enhances the αSynuclein Aggregation Process

“…Heat shock protein (Hsp) family members are molecular chaperones and function under both physiological and stress conditions. The failure of PN can lead to the accumulation of proteinaceous aggregates, which is a common event in different protein misfolding diseases such as Parkinson’s Disease (PD) and Alzheimer’s Disease (AD) [ 2 , 3 , 4 ].…”

Citicoline in Ophthalmological Neurodegenerative Disease: A Comprehensive Review

“…Neurons, as well as other post-mitotic cells, are particularly vulnerable to this kind of insult, since they experience a very accelerated metabolic activity and, at the same time, have not the possibility to dilute the wasting by-products through cell mitosis [ 46 , 47 ]. A paradigmatic example of a PN unbalance, in which the accumulation overrides the bulk degradative capacity, is the deposition of amyloidogenic proteins (e.g., Aβ peptide in AD, α-synuclein in PD, among the others) in the intracellular and extracellular compartments during the onset and progression of neurodegenerative diseases [ 48 , 49 ].…”

Therapeutics for dementia and Alzheimer's disease: New directions for precision medicine

“…One field of interest to some of these institutes is the targeting of proteostasis to facilitate the clearance of the misfolded proteins associated with neurodegenerative diseases. Newton, Duce, and Bayle () provide an overview of opportunities around modulation of chaperone activity by low molecular weight (MW) compounds, in order to target degradation either through the ubiquitin proteasome system (UPS) or chaperone mediated autophagy (CMA). Another field‐gaining interest in dementia for therapeutic targeting is neuroinflammation, a key feature in the progress of AD pathology into the “cellular phase” (De Strooper & Karran, ).…”