Abstract
In the past two decades, yeast models have delivered profound insights into basic mechanisms of protein misfolding and the dysfunction of key cellular pathways associated with amyotrophic lateral sclerosis (ALS). Expressing ALS-associated proteins, such as superoxide dismutase (SOD1), TAR DNA binding protein 43 (TDP-43) and Fused in sarcoma (FUS), in yeast recapitulates major hallmarks of ALS pathology, including protein aggregation, mislocalization and cellular toxicity. Results from yeast have consistently been recapitulated in other model systems and even specimens from human patients, thus providing evidence for the power and validity of ALS yeast models. Focusing on impaired ribonucleic acid (RNA) metabolism and protein misfolding and their cytotoxic consequences in ALS, we summarize exemplary discoveries that originated from work in yeast. We also propose previously unexplored experimental strategies to modernize ALS yeast models, which will help to decipher the basic pathomechanisms underlying ALS and thus, possibly contribute to finding a cure.
Highlights
In the past two decades, yeast models have delivered profound insights into basic mechanisms of protein misfolding and the dysfunction of key cellular pathways associated with amyotrophic lateral sclerosis (ALS)
Amyotrophic lateral sclerosis (ALS) is a heterogeneous neurodegenerative disease caused by loss of the upper motor neurons, i.e., neurons that extend from the cortex to the brain stem and the spinal cord and lower motor neurons, i.e., neurons that connect the brainstem or spinal cord to muscle (Hardiman et al, 2017)
Progressive loss of these neuron populations can manifest in two distinct early ALS symptoms: patients diagnosed with spinal-onset display a significant weakness of the limbs, whereas bulbar-onset leads to difficulty swallowing and difficulty speaking
Summary
RNA metabolism is a broad term encompassing the entire life cycle of all cellular RNAs, such as messenger RNA (mRNA), micro RNA (miRNA) and transfer RNA (tRNA) This includes RNA synthesis, modifications, folding and unfolding, processing and degradation, all of which are tightly regulated by multiple cellular pathways. There are 10 RBPs with known ALS mutations in their encoding genes: ANG, EWSR1, Fused in sarcoma (FUS), hnRNPA1, hnRNPA2B1, RGNEF, SETX, TAF15, TIA-1 and TAR DNA binding protein 43 (TDP-43; Table 1). These mutations lead to a broad range of deficits in RNA metabolism, including impaired transcription of both mRNAs and miRNAs, post-transcriptional modifications and RNA editing. TAF15 mislocalizes from the nucleus into the cytoplasm and is found in cytoplasmic inclusions, a common pathological hallmark in ALS proteinopathy, which is well-established for TDP-43 and FUS
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