Studies from Dr. Tao Wang's laboratory discover the mechanism of RACK1 in polyQ diseases

On May 13, 2021 ---- Dr. Tao Wang’s laboratory of National Institute of Biological Sciences, Beijing/Tsinghua Institute of Multidisciplinary Biomedical Research (TIMBR) published a new article titled “RACK1 modulates polyglutamine-induced neurodegeneration by promoting ERK degradation in Drosophila” online in PLOS Genetics. Researchers discovered scaffold protein RACK1 suppressed polyQ induced cell death through regulating ERK degradation.
Polyglutamine (polyQ) diseases are a group of diseases caused by CAG repeat expansion within causive genes. Currently there are nine types of polyQ diseases, including Spinocerebellar ataxia-3 (SCA-3) and Huntington's disease (HD). One common feature of these polyQ diseases is the formation of polyQ oligomers and aggregates in the cytosol and nucleus. Although more than 100 years have been spent on studying the pathogenesis of polyQ diseases, the mechanisms of how these mutant proteins induced neuronal death are still unknown.
To study the mechanism of polyQ induced cell death, we established a model of polyQ disease in the Drosophila eye, and conducted a forward genetic screen to identify suppressors of polyQ induced cell death. We found loss of RACK1 suppressed polyQ induced eye degeneration, and also SCA-3 and HD induced eye degeneration, suggesting rack1 suppressed polyQ diseases pathogenesis. Moreover, we found loss of RACK1 alleviated polyQ induced cell death without affecting the formation or clearance of polyQ aggregates.

(Figure 1 A: rack1 suppressed 63Q induced cell death; B: rack1 suppressed SCA-3 induced cell death；C: rack1 suppressed HD induced cell death; D-F: rack1 did not affect 63Q monomer and aggregates levels）

Through genomic wide RNAi screening, we found that knocking down E3 ligases POE further enhanced suppression of polyQ induced cell death by rack1. Further, overexpression of POE abolished the suppressive effects of rack1 mutation. Finally, we found that RACK1 regulated ERK level by promoting the interaction between ERK and POE.

(Figure 2 A: knocking down poe enhanced suppression of 63Q induced cell death by rack1; B: knocking down rack1 interrupt interaction between POE and ERK)

As previous studies found that the ERK pathway is inhibited in polyQ disease models, we hypothesize that the RACK1/POE/ERK pathway plays an important role in polyQ disease pathogenesis, and that this pathway should be considered a target for treating polyQ diseases.
Dr. Jun Xie and Dr. Yongchao Han are co-first authors of this article. Dr. Tao Wang is the corresponding author. The study was supported by the Chinese Ministry of Science and the Beijing municipal government, and was conducted at the National Institute of Biological Sciences, Beijing.

Full text link: https://doi.org/10.1371/journal.pgen.1009558