16Protein aggregation that results in the formation of inclusions is strongly correlated with 17 neuronal death and is a pathological hallmark common to many neurodegenerative diseases, 18including amyotrophic lateral sclerosis (ALS) and Huntington's disease. Cells are thought to 19 dramatically up-regulate the levels of heat shock proteins during periods of cellular stress via 20 induction of the heat shock response (HSR). Heat shock proteins are well-characterised 21 molecular chaperones that interact with aggregation-prone proteins to either stabilise, refold, 22 or traffic protein for degradation. The reason why heat shock proteins are unable to maintain 23 the solubility of particular proteins in neurodegenerative disease is unknown. We sought to 24 determine whether neurodegenerative disease-associated protein aggregates can induce the 25 HSR. Here, we generated a neuroblastoma cell line that expresses a fluorescent reporter 26 under conditions of HSR induction, for example heat shock. Using these cells, we show that 27 the HSR is not induced by exogenous treatment with aggregated forms of Parkinson's 28 disease-associated a-synuclein or the ALS-associated G93A mutant of superoxide 29 dismutase-1 (SOD1 G93A ). Furthermore, flow cytometric analysis revealed that intracellular 30 expression of SOD1 G93A or a pathogenic form of polyQ-expanded huntingtin (Htt 72Q ), similarly, 31 results in no or low induction of the HSR. In contrast, expression of a non-pathogenic but 32 aggregation-prone form of firefly luciferase (Fluc) did induce an HSR in a significantly greater 33 proportion of cells. Finally, we show that HSR induction is dependent on the intracellular levels 34 of the aggregation-prone proteins, but the pathogenic proteins (SOD1 G93A and Htt 72Q ) elicit a 35 significantly lower HSR compared to the non-pathogenic proteins (Fluc). These results 36 suggest that pathogenic proteins either evade detection or impair induction of the HSR in 37

Proteotoxic stress triggers transcriptional responses that allow cells to compensate for the accumulation of toxic misfolded proteins. Chromatin remodeling regulates gene expression in response to the accumulation of misfolded polyQ proteins associated with Huntington’s disease (HD). Tra1 is an essential component of both the SAGA/SLIK and NuA4 transcription co-activator complexes and is linked to multiple cellular processes associated with misfolded protein stress, including the heat shock response. Cells with compromised Tra1 activity display phenotypes distinct from deletions encoding components of the SAGA and NuA4 complexes, indicating a potentially unique regulatory role of Tra1 in the cellular response to protein misfolding. Here, we employed a yeast model of HD to define how the expression of toxic polyQ expansion proteins affects Tra1 expression and function. Expression of expanded polyQ proteins, mimics deletion of SAGA/NuA4 components and results in growth defects under stress conditions. Moreover, deleting genes encoding SAGA and, to a lesser extent, NuA4 components exacerbates polyQ toxicity. Also, cells carrying a mutant Tra1 allele displayed increased sensitivity to polyQ toxicity. Interestingly, expression of polyQ proteins also upregulated the expression of TRA1 and other genes encoding SAGA components, revealing a feedback mechanism aimed at maintaining Tra1and SAGA functional integrity. Moreover, deleting the TORC1 (Target of Rapamycin) effector SFP1 specifically abolished upregulation of TRA1 upon expression of polyQ proteins. While Sfp1 is known to adjust ribosome biogenesis and cell size in response to stress, we identified a new role for Sfp1 in the control of Tra1, linking TORC1 and cell growth regulation to functions of the SAGA acetyltransferase complex during misfolded protein stress.