Regulation of physiological and pathological condensates by molecular chaperones

Abstract

Biomolecular condensates are dynamic membraneless compartments that regulate a myriad of cellular functions. A particular type of physiological condensate called stress granules (SGs) has gained increasing interest due to its role in the cellular stress response and various diseases. SGs, composed of several hundred RNA-binding proteins, form transiently in response to stress to protect mRNAs from translation and disassemble when the stress subsides. Interestingly, SGs contain several aggregation-prone proteins, such as TDP-43, FUS, hnRNPA1, and others, which are typically found in pathological inclusions seen in autopsy tissues from amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) patients. Moreover, mutations in these genes lead to the familial form of ALS and FTD. This has led researchers to propose that pathological aggregation is seeded by aberrant SGs: SGs that fail to properly disassemble, lose their dynamic properties, and become pathological condensates which finally 'mature' into aggregates. Here, we discuss the evidence supporting this model for various ALS/FTD-associated proteins. We further continue to focus on molecular chaperone-mediated regulation of ALS/FTD-associated physiological condensates on one hand, and pathological condensates on the other. In addition to SGs, we review ALS/FTD-relevant nuclear condensates, namely paraspeckles, anisosomes, and nucleolar amyloid bodies, and discuss their emerging regulation by chaperones. As the majority of chaperoning mechanisms regulate physiological condensate disassembly, we highlight parallel themes of physiological and pathological condensation regulation across different chaperone families, underscoring the potential for early disease intervention.

Keywords: ALS; FTD; FUS; LLPS; TDP‐43; aggregation; chaperones; condensates; proteostasis; stress granules.

Fig. 1

Chaperone‐mediated regulation of physiological and pathological condensates. The diagram summarizes how different chaperone families (represented by colored circles) interact with stress granules (SGs), anisosomes/nuclear bodies, or paraspeckles, how they regulate condensation, and how they regulate pathological aggregation, based on the literature surveyed in this review. The figure summarizes evidence on mammalian chaperones only. Red lines denote inhibition, green lines denote activation, and gray lines represent inhibition of protein aggregation through processes related to autophagy. Black lines depict various processes: recruitment to condensates, translocation from nucleus to cytoplasm, condensate disassembly, and aggregation. Each chaperone family is presented separately, circled by a dashed line. Chaperones outside the SG border were not reported to colocalize with SGs; Chaperones inside SG border: colocalize with SG; Chaperones on SG border: mixed reports. See Table 1 for detailed literature support for each interaction. Semi‐transparent colors indicate chaperone colocalization with the SG based solely on large‐scale proteomic studies (Table 1B). FUS and TDP‐43 are shown in orange diamonds and blue squares, respectively, or in SGs with the respective colors.