Molecular Chaperones: A Double-Edged Sword in Neurodegenerative Diseases

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.

GAPDH is involved in the heme‐maturation of myoglobin and hemoglobin

“…It is well established that interplay between molecular chaperons is both cyclical and sequential to enable client protein maturation or initiate a misfolded protein response in healthy or diseased states respectively. [60][61][62] While cycling of molecular chaperons is a predictable event in the chaperoning of proteins, our current study suggests a unique synergistic role of an active sGC, heme bound-GAPDH and the molecular chaperon hsp90 or globin specific chaperons (e.g., AHSP) to enable heme-maturations of target globins. 26,27 This places globin maturations in a different class and indicates a tight regulation, which is in accord with previous concepts in globin maturation.…”

Redefining Molecular Chaperones as Chaotropes

“…In addition, even proteins that are capable of spontaneously reaching their native conformation may unfold under stress conditions. Folding intermediates or unfolded proteins are dysfunctional, prone to aggregation and may lead to fatal conditions that are a threat to the health of the cell ( Knowles et al, 2014 ; Tittelmeier et al, 2020 ).…”

α-Synuclein Strains: Does Amyloid Conformation Explain the Heterogeneity of Synucleinopathies?

“…Biochemical and high-resolution imaging techniques show that both pathological PrP Sc and α-Syn materials contain amyloid fibrils; however, their individual size, growth kinetics, frangibility, and environmental stability could differ, affecting their propagation capacity and ultimately determining disease dynamics and infectivity [133]. Greater accessibility of a given fibril structure to the cellular quality control system (e.g., chaperone networks) could lead to higher fibril fragmentation [134,135]. This could explain the pathological differences between the two disease classes, as small aggregates or oligomers in related amyloid proteins have been associated with accelerated spreading and higher toxicity [127].…”