Abstract
Many proteins involved in the pathogenic mechanisms of amyotrophic lateral sclerosis (ALS) are remarkably similar to proteins that form prions in the yeast Saccharomyces cerevisiae. These ALS-associated proteins are not orthologs of yeast prion proteins, but are similar in having long, intrinsically disordered domains that are rich in hydrophilic amino acids. These so-called prion-like domains are particularly aggregation-prone and are hypothesized to participate in the mislocalization and misfolding processes that occur in the motor neurons of ALS patients. Methods developed for characterizing yeast prions have been adapted to studying ALS-linked proteins containing prion-like domains. These yeast models have yielded major discoveries, including identification of new ALS genetic risk factors, new ALS-causing gene mutations and insights into how disease mutations enhance protein aggregation.
Highlights
Neurodegenerative diseases are defined by irreversible loss of neurons
These diseases manifest as dementias and movement disorders, depending on the subset of neurons that are principally affected
Since FUS, TDP-43, hnRNPA2, TATA-box binding protein associated factor 15 (TAF15) and ewing sarcoma breakpoint region 1 (EWS) each form cytoplasmic aggregates when ectopically expressed in yeast—much like naturally occurring yeast prion proteins—it has been straightforward to monitor how specific amyotrophic lateral sclerosis (ALS)-linked mutations alter the proteins’ intrinsic propensity to aggregate and exert toxicity, especially when coupled with in vitro aggregation assays
Summary
Neurodegenerative diseases are defined by irreversible loss of neurons. Clinically, these diseases manifest as dementias and movement disorders, depending on the subset of neurons that are principally affected. Since FUS, TDP-43, hnRNPA2, TAF15 and EWS each form cytoplasmic aggregates when ectopically expressed in yeast—much like naturally occurring yeast prion proteins—it has been straightforward to monitor how specific ALS-linked mutations alter the proteins’ intrinsic propensity to aggregate and exert toxicity, especially when coupled with in vitro aggregation assays. Similar to testing how disease-linked mutations can affect aggregation and toxicity of the full-length ALS proteins, site-directed mutagenesis of the fusion protein can be used to determine how any substitution may affect prion-like protein behavior This approach has been extensively performed with hnRNPA1 and hnRNPA2 in the lab of Eric Ross (Cascarina et al, 2018). This indicates that the ALS-linked proteins may be forming a type of amyloid that does not react strongly with Thioflavin T
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