Abstract
Neurodegenerative diseases (NDs) are increasingly positioned as leading causes of global deaths. The accelerated aging of the population and its strong relationship with neurodegeneration forecast these pathologies as a huge global health problem in the upcoming years. In this scenario, there is an urgent need for understanding the basic molecular mechanisms associated with such diseases. A major molecular hallmark of most NDs is the accumulation of insoluble and toxic protein aggregates, known as amyloids, in extracellular or intracellular deposits. Here, we review the current knowledge on how molecular chaperones, and more specifically a ternary protein complex referred to as the human disaggregase, deals with amyloids. This machinery, composed of the constitutive Hsp70 (Hsc70), the class B J-protein DnaJB1 and the nucleotide exchange factor Apg2 (Hsp110), disassembles amyloids of α-synuclein implicated in Parkinson’s disease as well as of other disease-associated proteins such as tau and huntingtin. We highlight recent studies that have led to the dissection of the mechanism used by this chaperone system to perform its disaggregase activity. We also discuss whether this chaperone-mediated disassembly mechanism could be used to solubilize other amyloidogenic substrates. Finally, we evaluate the implications of the chaperone system in amyloid clearance and associated toxicity, which could be critical for the development of new therapies.
Highlights
Neurodegeneration and Amyloid DepositionNeurodegenerative diseases (NDs) have a multifactorial etiology resulting from an intricate relationship between genetic and environmental factors [1]
Knockdown of the nucleotide-exchange factors (NEFs) in young individuals expressing either α-syn or 35 polyglutamine (Q35) fused to Yellow Fluorescence Protein (YFP) reduced foci formation and toxicity, and in the case of α-syn, it diminished cell-to-cell transmission. These results led the authors to propose that the Hsp70-based disaggregase could promote spreading via amyloid fragmentation to Hsp104, whose fragmentation activity [109,110] is essential for the maintenance of prions in yeast, producing smaller seeds that are more efficiently transmitted to daughter cells [111,112]
We have shown that the human disaggregase targets the most toxic amyloid species and disassembles them through an all-or-none depolymerization process [61], we have observed that depolymerization of longer fibrils is not as efficient and may be interrupted half-way through, producing shorter, and potentially more toxic, species [61]
Summary
Neurodegenerative diseases (NDs) have a multifactorial etiology resulting from an intricate relationship between genetic and environmental factors [1]. A histopathological hallmark of most NDs include the deposition of aggregated proteins called amyloids into extracellular or intracellular inclusions [2]. Misfolding and aggregation of proteins imply the loss of their native structure, and their physiological function. The generation and accumulation of misfolded protein species involves a gain of toxic function as these aggregation-prone species have a heightened tendency to engage in inappropriate interactions with other cellular components [2]. Through both mechanisms, aggregates alter fundamental cellular processes, leading to cell death
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