Abstract
Millions of people worldwide are affected by neurodegenerative diseases (NDs), and to date, no effective treatment has been reported. The hallmark of these diseases is the formation of pathological aggregates and fibrils in neural cells. Many studies have reported that catechins, polyphenolic compounds found in a variety of plants, can directly interact with amyloidogenic proteins, prevent the formation of toxic aggregates, and in turn play neuroprotective roles. Besides harboring amyloidogenic domains, several proteins involved in NDs possess arginine-glycine/arginine-glycine-glycine (RG/RGG) regions that contribute to the formation of protein condensates. Here, we aimed to assess whether epigallocatechin gallate (EGCG) can play a role in neuroprotection via direct interaction with such RG/RGG regions. We show that EGCG directly binds to the RG/RGG region of fused in sarcoma (FUS) and that arginine methylation enhances this interaction. Unexpectedly, we found that low micromolar amounts of EGCG were sufficient to restore RNA-dependent condensate formation of methylated FUS, whereas, in the absence of EGCG, no phase separation could be observed. Our data provide new mechanistic roles of EGCG in the regulation of phase separation of RG/RGG-containing proteins, which will promote understanding of the intricate function of EGCG in cells.
Highlights
Neurodegenerative diseases (NDs) affect millions of people worldwide and constitute a major public health threat
We found that epigallocatechin gallate (EGCG) directly binds to the RGG3-PY region of fused in sarcoma (FUS), with a non-specific/low-affinity behavior as observed by a linear increase in chemical shift perturbation (CSP) of FUS 1H15N cross-peaks upon EGCG addition
We proceeded to determine the influence of EGCG on the ability of methylated and unmethylated FUSRGG3PY to phase separate in the presence of RNA
Summary
Neurodegenerative diseases (NDs) affect millions of people worldwide and constitute a major public health threat. NDs occur when nerve cells in the brain or peripheral nervous system lose their function over time, leading to cellular death [1]. The hallmarks of these diseases, which encompass Alzheimer’s disease (AD), Parkinson’s disease (PD), amyotrophic lateral sclerosis (ALS), and frontotemporal dementia (FTD), are the formation of pathological aggregates and the presence of abnormal protein deposits in neural cells [2–5]. Several studies have demonstrated the role of green tea catechins in neuroprotection, with epigallocatechin gallate (EGCG) being widely studied because it constitutes 65% of all catechins in green tea [8–11]. The green tea catechins play a variety of roles in neuroprotection, such as exerting (i) anti-oxidative properties through radical scavenging and metal ion chelation [12–14], (ii) anti-apoptotic properties through the reduction in pro-apoptotic gene expression [15], (iii) anti-inflammatory properties through the inhibition of microglia activation [16], and (iv) anti-amyloidogenic properties through the remodeling of toxic
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