Differential regulation of physiological and pathological condensates by molecular chaperones and their isoforms

In recent years, an increasing number of cellular processes is being discovered as regulated by a variety of molecular condensates. Some of these can seed pathological forms, which turn into aggregates, associated with neurodegenerative diseases. Focusing on two such pathological condensates, the Huntington’s disease-associated HTT-polyQ and ALS-associated FUS, we found that HTT-polyQ aggregation induces a cellular proteotoxic stress response, while mutant FUS aggregation leads to deterioration in protein homeostasis (proteostasis), specifically manifested in downregulated expression of many chaperones. This finding has led us to ask whether chaperone induction is adaptive, and furthermore, whether the classical heat shock response can cope with the different aggregate types. Further screening the chaperone network for potential modifiers of aggregation, we identified specific chaperones which showed substantial protection from ALS-associated mutant FUS pathological condensation, in cell line models and in primary neurons. Interestingly, chaperone protection was not aligned with the cellular response to the different aggregate types. Thus, the cellular response to pathological aggregation was found to be maladaptive. Interestingly, we revealed divergent effects of naturally-occurring chaperone isoforms on different aggregate types; chaperones that were found to ameliorate FUS aggregation aggravated HTT-polyQ aggregation, while their short isoforms lost their inhibitory effect towards FUS aggregation, but were able to protect from HTT-polyQ aggregation. These findings further revealed a novel layer of chaperone network complexity conferred by chaperone isoforms, shown here to elicit different functional effects with respect to pathological condensation. Exploring chaperone isoforms in stress and disease reveals how chaperone network combinatorial complexity shapes cellular proteostasis.