Abstract
Upregulation of heat shock proteins (HSPs) is an approach to treatment of neurodegenerative disorders with impaired proteostasis. Many neurons, including motor neurons affected in amyotrophic lateral sclerosis (ALS), are relatively resistant to stress-induced upregulation of HSPs. This study demonstrated that histone deacetylase (HDAC) inhibitors enable the heat shock response in cultured spinal motor neurons, in a stress-dependent manner, and can improve the efficacy of HSP-inducing drugs in murine spinal cord cultures subjected to thermal or proteotoxic stress. The effect of particular HDAC inhibitors differed with the stress paradigm. The HDAC6 (class IIb) inhibitor, tubastatin A, acted as a co-inducer of Hsp70 (HSPA1A) expression with heat shock, but not with proteotoxic stress induced by expression of mutant SOD1 linked to familial ALS. Certain HDAC class I inhibitors (the pan inhibitor, SAHA, or the HDAC1/3 inhibitor, RGFP109) were HSP co-inducers comparable to the hydroxyamine arimoclomol in response to proteotoxic stress, but not thermal stress. Regardless, stress-induced Hsp70 expression could be enhanced by combining an HDAC inhibitor with either arimoclomol or with an HSP90 inhibitor that constitutively induced HSPs. HDAC inhibition failed to induce Hsp70 in motor neurons expressing ALS-linked mutant FUS, in which the heat shock response was suppressed; yet SAHA, RGFP109, and arimoclomol did reduce loss of nuclear FUS, a disease hallmark, and HDAC inhibition rescued the DNA repair response in iPSC-derived motor neurons carrying the FUSP525Lmutation, pointing to multiple mechanisms of neuroprotection by both HDAC inhibiting drugs and arimoclomol.
Highlights
Protein misfolding and aggregation are associated with multiple neurodegenerative disorders including amyotrophic lateral sclerosis (ALS)
The limited response of neurons to express HSP70 after heat shock: We previously reported that motor neurons in spinal cord-dorsal root ganglion (DRG) cultures have a high threshold for induction of a stress response in response to heat shock, such that thermal stress induces little or no Hsp70 (Batulan et al 2003), providing a good model to investigate how histone deacetylase (HDAC) inhibitors might overcome the high threshold for induction
We previously reported that chromatin remodeling is altered in cultured motor neurons expressing mutant FUS linked to familial ALS (Tibshirani et al 2015; Tibshirani et al 2017)
Summary
Protein misfolding and aggregation are associated with multiple neurodegenerative disorders including amyotrophic lateral sclerosis (ALS). Whereas phosphorylation of residues in HSF1’s regulatory domain was thought to be required for transactivational competence, more recent evidence points to a role in fine tuning of the heat shock response, including regulation of HSF1 binding to promoter elements (Budzynski et al 2015). Another regulatory factor is the translation elongation factor eEF1A1, which mediates stress-induced HSP70 (HSPA1A) transcription as well as stability and transport of HSP70 mRNA (Vera et al 2014). Motor neurons exhibit an underlying reticence for stress-induced activation of HSF1 (Batulan et al 2003) and the neuron-specific variant eEF1A2 lacks the regulatory ability of eEF1A1 (Vera et al 2014)
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