This will contribute to a better understanding, not only of which chaperones could be selected for drug development, but also of when to target these chaperones. Here, we will highlight the complex ways in which chaperones influence the different stages of prion-like propagation of proteins associated with the most prevalent neurodegenerative diseases. Chaperones are key regulators of amyloid formation since they monitor and prevent the misfolding and aggregation of proteins ( Kampinga and Bergink, 2016 Wentink et al., 2019). On a positive note, the age-dependent accumulation of amyloid deposits in neurodegenerative diseases suggests that in younger individuals there are PQC pathways active that can prevent aggregation. An age-related decline in the capacity of the PQC machinery appears to result in a proteostasis collapse ( Ben-Zvi et al., 2009), which in turn allows the manifestation of diseases associated with protein misfolding, such as the diseases mentioned above. When a protein escapes these (re)-folding or clearance mechanisms, misfolded forms accumulate and eventually aggregate ( Hartl et al., 2011). Molecular chaperones are key components of the PQC network and support cellular proteostasis by regulating the folding of nascent polypeptides, the re-folding of aberrant proteins, or their removal by degradation via the ubiquitin-proteasome system (UPS) or autophagy ( Bukau et al., 2006 Kampinga and Craig, 2010). Protein aggregates usually arise from the failure of the protein quality control (PQC) machinery that maintains cellular protein homeostasis (proteostasis). 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). Despite having different structures and functions under physiological conditions, under disease conditions, these proteins adopt a β-sheet-rich conformation with a strong tendency to form highly ordered amyloid fibrils. Each disorder is characterized by the misfolding of one or more specific proteins: amyloid-β (Aβ) and Tau (MAPT) in AD, α-synuclein (α-syn/SNCA) in PD, Huntingtin (HTT) in HD, superoxide dismutase 1 (SOD1), TAR DNA binding protein 43 (TDP-43/TARDBP), FUS RNA-binding protein (FUS) and dipeptide repeat proteins (DPRs) translated from C9orf72-SMCR8 complex subunit (C9orf72) in ALS, and the prion protein (PrP/PRNP) in prion diseases ( Dobson, 2017 Eisenberg and Sawaya, 2017). Understanding how chaperones alleviate and aggravate disease progression is vital for the development of therapeutic strategies to combat these debilitating diseases.Ī 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). 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. 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. With increasing age, however, the capacity of this proteostasis network tends to decrease, which enables the manifestation of neurodegenerative diseases. 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. 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. Pathological inclusions and the associated toxicity appear to spread through the nervous system in a characteristic pattern during the disease. German Cancer Research Center (DKFZ), Center for Molecular Biology of Heidelberg University (ZMBH), DKFZ-ZMBH Alliance, Heidelberg, GermanyĪberrant 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).Jessica Tittelmeier †, Eliana Nachman † and Carmen Nussbaum-Krammer *
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