Abstract
Protein misfolding and aggregation are implicated in many neurodegenerative diseases. One of these diseases is Huntington’s, which is caused by increased glutamine-encoding trinucleotide repeats within the Huntingtin gene. Like other misfolded proteins, mutated Huntingtin proteins with polyglutamine expansions are prone to aggregation. Misfolded proteins exist as soluble monomers, small aggregates, or as large insoluble inclusion bodies. Misfolded protein aggregates are believed to be cytotoxic by stressing the protein degradation machinery, disrupting membrane structure, or sequestering other proteins. We recently showed that expression of misfolded proteins lowers cellular free ubiquitin levels, which compromises the protein degradation machinery. Therefore, the efficient degradation of misfolded proteins is critical to preserve cell health. Cells employ two major mechanisms to degrade misfolded proteins. The first is the ubiquitin-proteasome system (UPS), which ubiquitinates and degrades misfolded proteins with the assistance of segregase Cdc48/p97. The UPS pathway is mainly responsible for the clearance of misfolded proteins present as monomers or smaller aggregates. The second pathway is macroautophagy/autophagy, in which protein aggregates or inclusion bodies are recruited into an autophagosome before transport to the vacuole/lysosome for degradation. This review is focused on the current understanding of the cytotoxicity of misfolded proteins as well as their clearance pathways, with a particular emphasis on mutant Huntingtin.
Highlights
One of these diseases is Huntington’s, which is caused by increased glutamine-encoding trinucleotide repeats within the Huntingtin gene
Chaperones, especially heat-shock proteins (Hsp) in the Hsp70 system, are responsible for refolding misfolded proteins. This function requires their binding to non-native proteins through a substrate binding domain (SBD), which is mediated by hydrogen bonds and van der Waals contacts with hydrophobic residues [20]
We found that cells with dysfunctional Cdc48 exhibited an increase of ubiquitinated proteins and protein aggregation, but showed decreased free ubiquitin levels, which leads to impaired degradation of other proteins via the ubiquitin-proteasome system (UPS) [47]
Summary
Misfolded protein aggregates take a variety of forms, with the main types being amorphous aggregates and organized amyloid structures, which are believed to be the cause of many neurodegenerative diseases. Most of these diseases are attributed to genetic variants in different genes, causing protein misfolding [1]. Human cells expressing mutant Htt with polyglutamine (polyQ) expansion produce pathogenic exon 1 fragments that contain the polyQ expansion, which is likely a result of proteolysis or alternative splicing [5,6] This polyQ expansion underlies the protein’s propensity for misfolding and aggregation. We discuss the nature of protein misfolding, the toxicity of misfolded protein aggregates, and mechanisms by which misfolded protein aggregates are cleared
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