Skip to main content
placeholder image

Neurodegenerative disease-associated protein aggregates are poor inducers of the heat shock response in neuronal-like cells

Journal Article


Abstract


  • Protein aggregation that results in the formation of inclusions is strongly correlated with neuronal death and is a pathological hallmark common to many neurodegenerative diseases, including amyotrophic lateral sclerosis (ALS) and Huntington’s disease. Cells are thought to dramatically up-regulate the levels of heat shock proteins during periods of cellular stress via induction of the heat shock response (HSR). Heat shock proteins are well-characterised molecular chaperones that interact with aggregation-prone proteins to either stabilise, refold, or traffic protein for degradation. The reason why heat shock proteins are unable to maintain the solubility of particular proteins in neurodegenerative disease is unknown. We sought to determine whether neurodegenerative disease-associated protein aggregates can induce the HSR. Here, we generated a neuroblastoma cell line that expresses a fluorescent reporter under conditions of HSR induction, for example heat shock. Using these cells, we show that the HSR is not induced by exogenous treatment with aggregated forms of Parkinson’s disease-associated α -synuclein or the ALS-associated G93A mutant of superoxide dismutase-1 (SOD1 G93A ). Furthermore, flow cytometric analysis revealed that intracellular expression of SOD1 G93A or a pathogenic form of polyQ-expanded huntingtin (Htt 72Q ), similarly, results in no or low induction of the HSR. In contrast, expression of a non-pathogenic but aggregation-prone form of firefly luciferase (Fluc) did induce an HSR in a significantly greater proportion of cells. Finally, we show that HSR induction is dependent on the intracellular levels of the aggregation-prone proteins, but the pathogenic proteins (SOD1 G93A and Htt 72Q ) elicit a significantly lower HSR compared to the non-pathogenic proteins (Fluc). These results suggest that pathogenic proteins either evade detection or impair induction of the HSR in neuronal-like cells. Therefore, defective HSR induction may facilitate the initiation of protein aggregation leading to inclusion formation in neurodegenerative diseases.

Publication Date


  • 2020

Citation


  • Gil, S., Cox, D., McAlary, L., Berg, T., Walker, A. K., Yerbury, J. J., . . . Ecroyd, H. (2020). Neurodegenerative disease-associated protein aggregates are poor inducers of the heat shock response in neuronal-like cells. doi:10.1101/2020.01.06.896654

Web Of Science Accession Number


Abstract


  • Protein aggregation that results in the formation of inclusions is strongly correlated with neuronal death and is a pathological hallmark common to many neurodegenerative diseases, including amyotrophic lateral sclerosis (ALS) and Huntington’s disease. Cells are thought to dramatically up-regulate the levels of heat shock proteins during periods of cellular stress via induction of the heat shock response (HSR). Heat shock proteins are well-characterised molecular chaperones that interact with aggregation-prone proteins to either stabilise, refold, or traffic protein for degradation. The reason why heat shock proteins are unable to maintain the solubility of particular proteins in neurodegenerative disease is unknown. We sought to determine whether neurodegenerative disease-associated protein aggregates can induce the HSR. Here, we generated a neuroblastoma cell line that expresses a fluorescent reporter under conditions of HSR induction, for example heat shock. Using these cells, we show that the HSR is not induced by exogenous treatment with aggregated forms of Parkinson’s disease-associated α -synuclein or the ALS-associated G93A mutant of superoxide dismutase-1 (SOD1 G93A ). Furthermore, flow cytometric analysis revealed that intracellular expression of SOD1 G93A or a pathogenic form of polyQ-expanded huntingtin (Htt 72Q ), similarly, results in no or low induction of the HSR. In contrast, expression of a non-pathogenic but aggregation-prone form of firefly luciferase (Fluc) did induce an HSR in a significantly greater proportion of cells. Finally, we show that HSR induction is dependent on the intracellular levels of the aggregation-prone proteins, but the pathogenic proteins (SOD1 G93A and Htt 72Q ) elicit a significantly lower HSR compared to the non-pathogenic proteins (Fluc). These results suggest that pathogenic proteins either evade detection or impair induction of the HSR in neuronal-like cells. Therefore, defective HSR induction may facilitate the initiation of protein aggregation leading to inclusion formation in neurodegenerative diseases.

Publication Date


  • 2020

Citation


  • Gil, S., Cox, D., McAlary, L., Berg, T., Walker, A. K., Yerbury, J. J., . . . Ecroyd, H. (2020). Neurodegenerative disease-associated protein aggregates are poor inducers of the heat shock response in neuronal-like cells. doi:10.1101/2020.01.06.896654

Web Of Science Accession Number