About this Research Topic

Background

Under normal physiological conditions protein folding is governed by quality control mechanisms that distinguishes between correctly folded proteins from those that have not attained their full functional conformation, resulting in their elimination from the cell. Regulation of protein folding, largely associated with the endoplasmic reticulum (ER), operates through a network of co-ordinated responses that involves thiol-disulfide oxidoreductases such as protein disulphide isomerase (PDI) and ERp57, Ero1, lectins (e.g. Calnexin), the N-glycan processing enzymes and molecular chaperones including glucose-regulated protein (GRP78/Bip), one of the heat shock proteins (HSP70).
Under cellular stress, the ER responds through the unfolded protein response (UPR), an adaptive mechanism, which functions to prevent the build-up of protein aggregates. However, when this system is overwhelmed, as observed with persistent or severe cellular stress, there is a loss in the structural integrity and function of the ER that ultimately leads to apoptotic cell death. This mechanism may play an important role in the development of many neurological disorders.

In addition to the UPR, autophagy, a cellular mechanism involved in protein degradation, recycling, and elimination of unwanted, damaged cell debris, has a primary role to protect cells under stress. Although autophagy serves to protect and preserve the cell, recent studies have suggested that dysregulation in this mechanism has been linked to the increased levels of protein mis-folding observed in neurodegenerative conditions such as Alzheimer’s disease (AD). Not only are aggregates such as amyloid-β and hyper phosphorylated tau characteristic of brain pathology in AD, most neurodegenerative conditions are associated with protein aggregation, such as α-synuclein and synphillin-1 in Parkinson’s disease, inclusion bodies associated with amylotrophic lateral sclerosis (ALS), aggregated Huntingtin’s protein in Huntington’s disease (HD) and prions, infectious misfolded proteins, which are responsible for transmissible spongiform encephalopathy’s. Interestingly, various models of these disease mechanisms have reported that molecular chaperones such as heat shock proteins (HSP70 and HSP90) and PDI are upregulated in response to cellular stress. However, redox sensitive proteins like PDI are thought to be modified through S-nitrosylation, which may impact protein function, compromising their protective role. Therefore, the importance of the redox environment in regulating protein mis-folding is core to our understanding of these pathogenic mechanisms.

In this series we critically explore and discuss the importance of correct cellular protein folding but also debate the potential mechanisms which contribute to cellular aggregates observed in each of the neurological disorders described. Understanding these mechanisms will be pivotal to ‘unfolding’ pathogenic pathways, potentially discovering new therapeutic targets that could slow down disease progression and also offer insight into novel biomarkers to detect early onset and differentiate between mild-cognitive impairment and patients who will develop dementia.

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