Abstract
Aberrant accumulation of misfolded proteins into amyloid deposits is a hallmark in many age-related neurodegenerative diseases, including Alzheimer’s disease (AD), Parkinson’s disease (PD), Huntington’s disease (HD), and amyotrophic lateral sclerosis (ALS). Pathological inclusions and the associated toxicity appear to spread through the nervous system in a characteristic pattern during the disease. This has been attributed to a prion-like behavior of amyloid-type aggregates, which involves self-replication of the pathological conformation, intercellular transfer, and the subsequent seeding of native forms of the same protein in the neighboring cell. Molecular chaperones play a major role in maintaining cellular proteostasis by assisting the (re)-folding of cellular proteins to ensure their function or by promoting the degradation of terminally misfolded proteins to prevent damage. With increasing age, however, the capacity of this proteostasis network tends to decrease, which enables the manifestation of neurodegenerative diseases. Recently, there has been a plethora of studies investigating how and when chaperones interact with disease-related proteins, which have advanced our understanding of the role of chaperones in protein misfolding diseases. This review article focuses on the steps of prion-like propagation from initial misfolding and self-templated replication to intercellular spreading and discusses the influence that chaperones have on these various steps, highlighting both the positive and adverse consequences chaperone action can have. Understanding how chaperones alleviate and aggravate disease progression is vital for the development of therapeutic strategies to combat these debilitating diseases.
Highlights
A common feature in many neurodegenerative diseases, including Alzheimer’s disease (AD), Parkinson’s disease (PD), Huntington’s disease (HD), amyotrophic lateral sclerosis (ALS), and prion diseases is the age-related formation of amyloid deposits (Chiti and Dobson, 2017)
These fibrils can act as pernicious templates for the native monomeric form of the respective protein to misfold into the amyloid conformation and incorporate into the growing fibrils, which eventually accumulate into large intra- and/or extracellular deposits characteristic for the respective neurodegenerative diseases (Jucker and Walker, 2013)
They can dissociate protein aggregates by extracting individual monomers (Mogk et al, 2018). Both these processes can eventually help the substrates to regain their native folding state. If this does not succeed, chaperones can control the sequestration of misfolded protein species in a way that prevents harmful interactions with the rest of the proteome (Miller et al, 2015)
Summary
A common feature in many neurodegenerative diseases, including Alzheimer’s disease (AD), Parkinson’s disease (PD), Huntington’s disease (HD), amyotrophic lateral sclerosis (ALS), and prion diseases is the age-related formation of amyloid deposits (Chiti and Dobson, 2017). While chaperone-mediated disaggregation seems to significantly contribute to the toxicity associated with pathological α-syn, it is essential for the maintenance of cellular proteostasis, as reducing HSP-110 levels compromised the overall cellular protein folding environment (Tittelmeier et al, 2020).
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